Recent Advances in the Chemistry of Pentafulvenes - Chemical

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Recent Advances in the Chemistry of Pentafulvenes Preethanuj Preethalayam,† K. Syam Krishnan,† Sreeja Thulasi,† S. Sarath Chand,† Jomy Joseph,‡ Vijay Nair,*,† Florian Jaroschik,*,‡ and K. V. Radhakrishnan*,† †

Organic Chemistry Section, National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Trivandrum 695 019, Kerala, India ‡ Institut de Chimie Moléculaire de Reims CNRS (UMR 7312) and Université de Reims Champagne-Ardenne, Reims 51687 Cedex 2, France ABSTRACT: Pentafulvenes are a unique class of compounds that originally attracted attention due to their propensity to display nonbenzenoid aromaticity. Subsequently, they were recognized as valuable synthons for the construction of a wide range of compounds by virtue of their ability to display multiple cycloaddition profiles. Naturally, this area of organic chemistry has experienced rapid growth over the last five decades, fueled by elegant work showcasing the unique reactivity of pentafulvenes in a plethora of cycloaddition reactions. In this Review, we have attempted to provide a systematic account of the methods for the generation of pentafulvenes, their rich and varied cycloaddition chemistry, organometallic reactions, and theoretical studies that support their versatility. Further, we have highlighted their applications in the synthesis of a variety of complex structural frameworks. It is our conviction that this Review will be useful to a wide range of chemists, and will spur further research in this promising area.

CONTENTS 1. Introduction 2. Fundamental Properties of Pentafulvenes 2.1. Bond Length Alternation and Aromaticity: Substituent Effects 2.2. General Reactivity Patterns 3. Synthesis of Pentafulvenes 3.1. Extension of Conventional Methods 3.2. Transition Metal-Catalyzed Reactions 3.3. Miscellaneous Reactions 4. Cycloaddition Chemistry of Pentafulvenes 4.1. Pentafulvene as 2π Components 4.2. Pentafulvenes as 4π Components 4.3. Pentafulvene as 6π Components 4.4. Pentafulvenes in Dipolar Cycloaddition Reactions 4.5. Cycloadditions of 6-Dimethylaminofulvenes and Fulvene Ketene Acetals 5. Miscellaneous Reactions of Pentafulvenes 5.1. Epoxidation of Fulvenes 5.2. Transformations of 6,6-Dicyanofulvenes: Isomerization to Benzene and [2+2] Cycloaddition−Retroelectrocyclization Reactions 5.3. Frustrated Lewis Pair (FLP) Chemistry of Pentafulvenes 5.4. Hydroheteroarylation of Pentafulvenes 5.5. Oxidative Addition of Pentafulvene 5.6. Chiral Pentafulvene as Brønsted Acid Catalyst in Organic Transformations 5.7. Other Reactions 6. Pentafulvenes in Metallocene Chemistry © 2017 American Chemical Society

6.1. Pentafulvenes as Precursors for Cp ligands 6.1.1. Reductive Complexation 6.1.2. Carbometalation Reactions 6.1.3. Addition of Nitrogen or Phosphorus Nucleophiles onto Pentafulvenes 6.1.4. Reductive Dimerization of Pentafulvenes 6.1.5. Deprotonation α to the C6 Position 6.1.6. Miscellaneous 6.2. Pentafulvenes as Ligands in Organometallic Complexes 6.2.1. Synthesis by Neutral Ligand Displacement 6.2.2. Reduction of Metal Precursors in the Presence of Pentafulvenes 6.2.3. Generation of Pentafulvenes in the Coordination Sphere of Metals 6.2.4. Miscellaneous Organometallic Complexes with Pentafulvenes 6.3. Transformation of Pentafulvenes via MetalCatalyzed Reactions 6.3.1. Unusual Cycloaddition Partners of Pentafulvenes: Fischer−Carbene Complexes 6.3.2. Hydrometalation Reactions of Pentafulvenes 7. Theoretical Perspectives and Photophysical Properties of Pentafulvenes 7.1. Aromaticity and Substitution Effects 7.2. Photophysical Properties of Pentafulvenes

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Received: April 4, 2016 Published: February 2, 2017 3930

DOI: 10.1021/acs.chemrev.6b00210 Chem. Rev. 2017, 117, 3930−3989

Chemical Reviews 7.3. Nonlinear Optical Properties 8. Conclusion Author Information Corresponding Authors ORCID Present Addresses Notes Biographies Acknowledgments References

Review

studies aimed at understanding their reactivity patterns. These pioneering works have been very carefully and elegantly reviewed by Day in 1953,14 Bergmann in 1968,15 Yates in 1968,16 Zeller in 1985,17 and subsequently by Neuenschwander in 1989.2 However, despite the evolution of much new chemistry in this area in recent years, there exists no extensive review detailing the rich chemistry of pentafulvenes. In this Review, we present a comprehensive survey of the developments in this area, giving a critical account of synthetic transformations, organometallic chemistry, metal-catalyzed reactions, and a short section on the theoretical and photophysical properties of pentafulvenes. We have incorporated the synthetic routes to pentafulvenes from the classical methods up to the latest reports. The use of pentafulvene in the synthesis of polycycles, natural products, and various organometallic complexes is discussed in detail. In addition, progress in the theoretical aspects of pentafulvenes and their emergence in the area of organic electronics is detailed in this Review. This Review covers the chemistry of pentafulvenes from 1984 to April 2016. Other types of fulvenes, that is, benzofulvenes, dibenzofulvenes, triafulvenes, heptafulvenes, pentalenes, and fulvalenes, etc., are certainly interesting compounds; however, for the sake of coherence, we have restricted our discussion mainly to advances in the chemistry of pentafulvenes obtained from cyclopentadiene (and their derivatives) by excluding the analogous compounds derived from indene and fluorene and other systems in which benzenoid ring is fused to the fulvene ring.

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1. INTRODUCTION Fulvenes constitute a fascinating class of organic compounds that display a unique π-electron system predicated by their cyclic cross-conjugated disposition.1 In accordance with the size of the ring system, they are classified as either tria-, penta-, hepta-, or nonafulvenes.2 The initial enthusiasm for research into fulvenes may be attributed to their potential for displaying non benzenoid aromaticity; for instance, pentafulvene is a cyclic isomer of benzene with nonbenzenoid aromaticity and high polarizability. However, due to their chemical instability, fulvenes have for a long time been considered to be nonaromatic.3 Importantly, the aromatic character of pentafulvene 1 is markedly dependent on the electronic nature of the substituents at the exocyclic position.4,5 Electron-donating groups strongly stabilize the ring, leading to substantial increases in aromatic character, in keeping with the tendency to satisfy the Hückel 4n+2 rule. Pentafulvenes were among the first known colored hydrocarbons and are unique in their reactivity toward electrophiles, nucleophiles, cycloaddition partners, and metals. They are also noteworthy for their electronic structure, optical properties, and applications in various fields. Scientists have always been keen to gain insight into the theoretical and practical challenges associated with this system in fundamental and applied research. The atoms in pentafulvenes are numbered in three different ways: the Chemical Abstracts numbering is the most commonly used system (Figure 1a), whereas some authors still use the

2. FUNDAMENTAL PROPERTIES OF PENTAFULVENES Pentafulvenes are well-known isomers of benzene; however, they exhibit exceptional reactivity when compared to the latter. The name “fulvene” is derived from the Latin word “fulvus” meaning yellow, and is the color of simple alkyl fulvenes. The color of pentafulvenes is due to their cross conjugation and varies with substitution: the color gets darker by substitution with arenes, heteroatoms, or cyano groups. The substitution of an aromatic group directly onto the ring is less effective in deepening the color than adding groups onto the exocyclic carbon. Undoubtedly, the most prominent feature of pentafulvene is the relatively high polarization of the exocyclic olefin and the resulting electropositive character at the exocyclic carbon atom. When compared to open-chain olefinic molecules and delocalized aromatic systems, fulvenes have bond lengths that strongly alternate between the two extremes.18 It was this behavior that attracted experimental chemists to study the reactivity patterns of pentafulvenes. Now pentafulvenes have secured their position as “wonder molecules” in the hands of scientists, with properties such as alternating bond lengths, dipole moment, aromaticity, as well as a versatile reactivity profile and applications.

Figure 1. Dipolar structure of parent pentafulvene.

Beilstein numbering (Figure 1b). In some other cases, fulvenes are named as derivatives of cyclopentadiene; dimethylfulvene is referred to as isopropylidene cyclopentadiene. In this Review, the Chemical Abstracts nomenclature is followed. Contemporaneous to the theoretical interest in pentafulvenes, their synthetic aspects have ignited the imagination of organic chemists and motivated researchers to exploit the diverse cycloaddition possibilities offered by the compounds. Consequently, pentafulvenes have served as key intermediates in the synthesis of natural and unnatural compounds such as hirsutene, capnellene, β-vetivone, and many aminocyclopentitols endowed with glycosidase inhibitory activity.6−11 Ever since their discovery in 1900,12,13 a number of procedures for the synthesis of pentafulvenes have been reported, along with

2.1. Bond Length Alternation and Aromaticity: Substituent Effects

The definition of aromaticity, and how to measure it, has occupied theoretical and experimental scientists for decades. In recent years, new universal aromaticity measures developed by theoreticians have been proposed.19,20 From an experimental point of view, bond length alternation (BLA) is an excellent criterion by which one can predict whether a cyclic conjugated molecule is olefinic or aromatic. BLA is defined as the average of the difference in the length between adjacent carbon−carbon bonds in a polyenic chain.21 Information about BLA can be provided by X-ray and MW spectroscopy22 as well as by NMR 3931


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Table 1. Structures and Spectroscopic Data of Some Pentafulvenes

fulvene data X-ray/MW (Å)

BLA (Å) 1 H NMR (δ ppm) 3

JHH (Hz)

13

C NMR (δ ppm)

C1−C2/C3−C4 C2−C3 C1−C5/C4−C5 C5−C6 C6−Cα Torsion angle C5−C6 bond (°) C1 → C6 H1/4 H2/5 J1,2 J2,3 C1/4 C2/3 C5 C6

dipole moment (D) UV spectrum λmax (cm−1)

122,24,32

229,35

337

429,36

540

641

1.355 1.476 1.470 1.348 − − 0.12 6.22 6.53 5.10 1.95 124.9 134.3 152.6 123.4 0.424 360

1.346 1.439 1.435 1.343 1.520 0 0.09 6.50 6.38 5.32 2.13 120.4 130.4 142.7 148.7 1.1 270, 365

1.347 1.43 1.457 1.366 1.472 11 0.09 − − − − 123.9 128.8 139.5 154.4 − 267, 298, 393

1.363/1.388 1.416 1.431 1.407 − 29 0.04 6.12 5.92 4.36 2.58 115.8 116.8 106.4 164.5 5.4 254, 342

1.374/1.381 1.410 1.417/1.422 1.430 − 32 0.03 6.04 6.1940 − − 110.4 111.2 98.0 148.3 − 254, 338

1.356 1.507 1.478 1.366 1.445 10 0.13 − − − − 151.3 132.6 168.7 86.7 − 270, 387, 543

Because of this effect, the NMR signals of a molecule that is inplane and outside the ring experience downfield shifts, while protons within or slightly above the ring undergo upfield shifts. Unfortunately, this phenomenon cannot be applied to determine the aromaticity of the fulvenes because the increasing πdelocalization or aromaticity is related to the increasing importance of the dipolar structure. Furthermore, the charge density variation will also influence their 13C and 1H shifts (Table 1).28−32 The influence of charge density and dipolar structure can be predicted by the ring current effects. It is interesting to monitor the substitution effect on the aromaticity of pentafulvenes, because the parent pentafulvene is known to be nonaromatic. Early experimental works and measured dipole moments of substituted fulvenes indicate that substitution can considerably increase the π-delocalization such that the corresponding derivatives may occupy a position intermediate between the nonaromatic and aromatic molecules (Table 1).16,18 Thus, by varying the substituents, the πdelocalization and charge distribution can be changed without significant steric effects. In the case of pentafulvene, the same can be enhanced by placing electron-donating substituents at the exocyclic carbon, and the effect can be observed directly by Xray35−41 and indirectly by NMR spectroscopy (Table 1). With the increase in the electron-donating capacity of the substituent at the C6 position, the formal double bonds are lengthened while the formal single bonds are shortened, the most extreme example to date being the imidazolium-based fulvene 5. In contrast, placing electron-withdrawing groups in the 6-position (fulvene 6) leads to an inversion of polarity at the exocyclic double bond as seen from the 13C NMR spectra and, as compared to the parent pentafulvene, an even more explicit diene system in the

techniques. Infrared spectroscopy was shown to have little utility in determining the aromaticity of fulvenes.23,24 In the UV spectrum, the bathochromic shift of the longest wavelength absorption from triafulvene to pentafulvene corresponds to the extension of the conjugative system (Table 1).24−26 Neuenschwander has extensively studied fulvenes by NMR spectroscopy,27−32 showing that (i) the proton chemical shifts of the planar pentafulvene are in the olefinic region and the effect of substitution on the endocyclic ring is negligible, (ii) the vicinal H,H coupling constants (3JHH) of the ring protons are strongly alternating for pentafulvenes (Table 1), and (iii) the 1JCC coupling constants of adjacent carbon atoms in the fulvene ring are also alternating. The latter is an interesting point, as 1JCC are not easily accessible due to the small concentration of isotopomers with two adjacent 13C atoms in the fulvene molecule. On the basis of these experiments, it can be concluded that the C−C bond lengths in the fulvene ring alternate strongly. This phenomenon is confirmed by using microwave spectroscopy22 and X-ray crystallographic data, which allow the calculation of BLA values for different fulvenes (Table 1): the calculated average of the absolute value of BLA for the parent fulvene (0.12 Å) is comparable to that of polyenes, such as polyethylene (0.11 Å), whereas this value decreases to 0.04−0.03 Å for more aromatic pentafulvenes bearing electron-donating groups at the C6 position (fulvenes 4 and 5; for example, see Table 1). In addition to the BLA, it is possible to characterize highly delocalized aromatic molecules by the high mobility and polarizability of their π-electron cloud. Thus, diamagnetic susceptibility can be taken as a tool for the prediction of aromaticity.33 However, the most notable effect is the “ring current effect”34 induced by delocalized aromatic π-systems. 3932


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Figure 2. (a) HOMO−LUMO representation of pentafulvene. (b) Influence of substituents on the energy of frontier orbitals. (c) Schematic of the reactivity of pentafulvenes toward nucleophiles, electrophiles, and base. Reproduced (adapted) with permission from ref 2. Copyright 1989 John Wiley and Sons.

ring, with X-ray studies indicating that the longest bond is that between C2 and C3. These results clearly indicate that even though the parent pentafulvene has nonaromatic character, π substitution at the exocyclic position can alter the aromaticity of fulvenes considerably. This property is also supported by theoretical calculations, and a detailed overview is presented in section 7.

erations also give an idea of the cycloaddition profile of pentafulvenes. Dienophiles with low-energy LUMOs are expected to have a strong interaction with the HOMO of pentafulvene. The substituents at the exocyclic position will determine the energy of the LUMO, and that will decide in which manner the pentafulvene will act in its cycloaddition profile.27 A detailed analysis of the substitution effects and reactivity is given in the succeeding sections. In addition, pentafulvenes having alkyl substituents in the exocyclic position can be readily transformed into the corresponding vinylcyclopentadienyls by employing strong bases. This transformation has been applied in cycloaddition and organometallic chemistry to widen the scope of fulvene chemistry.

2.2. General Reactivity Patterns

Most fulvenes react readily with both electrophiles and nucleophiles. Insight into the reactivity of fulvenes can be obtained from frontier orbital considerations.42,43 Pentafulvene, when compared to its isomer benzene, has a high-energy HOMO (highest occupied molecular orbital) and a comparably lowenergy LUMO (lowest unoccupied molecular orbital), as evidenced from the long wavelength absorption of fulvene and its color. One of the frontier orbitals of fulvene has a nodal plane passing through the exocyclic bond, so that energy of that molecular orbital remains unaltered by the exocyclic substituent (Figure 2a). This difference in the HOMO and LUMO accounts for the reactivity, electronic nature, as well as the low thermal stability of the fulvenes when compared to other aromatics. Normally, a high-energy HOMO of one substrate is expected to have a strong interaction with the LUMO of another substrate, if the orbitals have the same symmetry on a symmetry element that is common to the reactants, and vice versa. Electrophiles usually have a low-energy LUMO and strongly interact with the HOMO of the pentafulvene, while nucleophiles possessing a high energy HOMO are expected to have a strong binding interaction with the LUMO of the pentafulvene. The exocyclic substituent has a strong influence on the LUMO of pentafulvenes. −M substituents lower the energy of LUMO, and the effect is the opposite if the substituent has a +M effect (Figure 2b). In fact, considering the LUMO of pentafulvene, the C6 has the largest Hückel coefficient, and nucleophiles will attack the exocyclic position. Yet in the case of the HOMO of pentafulvene, electrophiles are expected to react predominantly at the C1/C4 position (Figure 2c). Frontier orbital consid-

3. SYNTHESIS OF PENTAFULVENES As stated above, a large number of synthetic procedures to access pentafulvenes and fulvene derivatives have been developed,14−17,44−46 either by a simple condensation of cyclopentadiene with ketones or aldehydes (Scheme 1) or by a transition metal-mediated reaction. The most commonly used method for the preparation of pentafulvene is the condensation of cyclopentadiene with aldehydes or ketones in the presence of sodium ethoxide in ethanol, which was developed by Thiele et al.12,13 Here, the base acts both as a deprotonating agent and also as a catalyst in the dehydration step. The reaction is fast and easily monitored by the appearance of yellow to red color. This method is suitable for reactions involving aliphatic and alicyclic ketones; however, it gives poor results with diaryl, aryl alkyl ketones, and aliphatic aldehydes. Stone and Little significantly improved the method by employing secondary amines, particularly pyrrolidine, as bases.47−49 This synthesis is readily carried out at room temperature using a wide range of aliphatic and aromatic aldehydes, as well as aliphatic ketones. Here, pyrrolidine acts not only as a base but also as a precursor for the iminium ion to catalyze the addition step, thus rendering the carbonyl carbon more electrophilic. An alternative synthetic pathway using 3933


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pentafulvenes by the reaction of N,N-dialkylamides 13 or dimethyl carbamyl chloride with organolithium compounds 14 and cyclopentadiene. This method does not require the ketone intermediate to be isolated (Scheme 2). The effect of the base and the steric hindrance of the reactants in the conventional synthesis of pentafulvene (the Little and Thiele procedure) was extensively studied by Erden and coworkers.58 They found that aldehydes and dialkyl ketones were the best variants in Little’s method. From their observation, it is clear that the elimination step is the rate-determining step; thus, while using a weak base, fragmentation to the reactant will compete with the elimination route, whereas in the case of a strong base, such as hydroxide or alkoxides, the dehydration step is enhanced, thereby favoring the formation of fulvene. In the case of sterically hindered α,β-unsaturated ketones, 1,2 addition predominates when a strong base is used. These findings were helpful in identifying suitable bases for the synthesis of different fulvenes. Later, researchers efficiently utilized the improved method proposed by Roesky and co-workers59 for the synthesis of sodium and potassium cyclopentadienide in the preparation of 6,6′-disubstituted pentafulvene by condensation with ketones.60 The progress of the reaction can be monitored by observing the color change in the reaction mixture. Dougherty and co-workers prepared fulvene ketones 17 in good yields; these can be converted into the corresponding bisfulvenes 18 by reaction with CpMgBr.61 The problem of enolization was solved by blocking the second position using a methyl group (Scheme 3).

Scheme 1. Conventional Methods for Pentafulvene Synthesis

aliphatic, α,β-unsaturated, and aromatic aldehydes was reported by Neuenschwander by the reaction of an acyl halide with an aldehyde.50 The Lewis acid-mediated reaction generates 1acetoxy-1-halomethanes, which react with cyclopentadiene in the presence of tertiary amines (e.g., triethylamine), leading to the pentafulvene. The synthesis of electron-rich diaminopentafulvenes was first developed by Meerwein and Hafner in the reaction of dimethylformamide diethylacetals with cyclopentadiene.51−55 As a notable advancement in the synthesis of pentafulvenes, Erden and Coskun put forward an efficient catalytic method for the synthesis of fulvene using catalytic amounts of pyrrolidine in MeOH/H2O. This method allows the use of smaller amounts of cyclopentadiene and base as compared to the conventional syntheses.56 The various protocols that emerged are discussed in the following sections.

Scheme 3. Preparation of a Fulvene Ketone and a Bisfulvene

3.1. Extension of Conventional Methods

The main limitations encountered in the conventional fulvene synthesis are the strong alkaline conditions, the limited availability of various substituted cyclopentadienes, as well as the low reactivity of available cyclopentadienes. In their attempts to synthesize oligomers of 6-(2-thienyl)pentafulvene, Kurata et al.57 came across difficulties due to the low solubility as well as the instability of the product with increasing numbers of monomer units. To avoid this, they devised a one-pot synthesis of

An exceptionally simple and efficient synthesis of 6-methyl-6vinylfulvene 21 was developed by Erden and Gärtner (Scheme 4).62 Later, the authors devised a convenient three-step protocol

Scheme 2. Reaction of N,N-Dialkylamides with Organolithium Compounds

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Scheme 4. Strategies for the Preparation of 6-Vinylfulvenes

Scheme 6. Palladium-Catalyzed Reaction of Vinylic Halides with Disubstituted Alkynes

utilizing a sulfide oxidation and subsequent sulfoxide elimination strategy.63 This protocol offers an excellent strategy for the synthesis of unsubstituted and substituted 6-vinylfulvene (Scheme 4). During their synthesis of imidazolium-substituted metallocenes, Kunz et al. prepared imidazoline-based fulvenes (5, see section 2.1) as precursors by using a modified version of the route used by Meerwein and Hafner.40 During the course of the synthesis of a homogeneous Ziegler catalyst for polymerization, Erker and co-workers effectively utilized a previous literature procedure by Hafner for the synthesis of 6-amino-6-methylfulvene and some derivatives.64,65

affect this reaction. Subsequently, a palladium/base-mediated catalytic system for the 1:2 coupling of vinyl bromides with diarylacetylenes was developed to produce pentaarylfulvenes.71 Palladium-catalyzed cyclic carbopalladation was also used to prepare fulvenes 33 in an intermolecular fashion (Scheme 7).72 Scheme 7. Palladium-Catalyzed Cyclic Carbopalladation

3.2. Transition Metal-Catalyzed Reactions

Transition metal-catalyzed bond formation represents a vital tool in target-oriented synthesis. Transition metal-catalyzed synthesis affords pentafulvenes with diverse substituents in the endocyclic ring. A new and general synthesis of substituted fulvenes 28 was established, based on the palladium-catalyzed [2+2+2] annulation of β-substituted vinyl iodide 26 and monosubstituted alkyne 27 (Scheme 5) by Lee et al.66

To expand the scope of the site-selective palladium-catalyzed coupling of 1,4-diiodo-1,3-alkadienes with Grignard reagents, a regio- and stereoselective synthesis of 1,3,6-trisubstituted fulvenes, including those with Z-exocyclic double bonds, was established.73 The [2+2+1] cyclotrimerization of alkynes was also reported for other transition metals (see section 6.2.3). The trimerization of tert-butylacetylene catalyzed by titanium aryloxide generated 1,3,6-tri(tert-butyl)fulvene.74 In 2011, Tanaka and co-workers devised an unusual Rh-catalyzed [2+2+1] cross-cyclotrimerization of two different alkynes, silylacetylene 34 and alkynyl esters 35, leading to the formation of substituted silylfulvenes 36 (Scheme 8).75

Scheme 5. Palladium-Catalyzed [2+2+2] Annulation of βSubstituted Vinyl Iodides and Monosubstituted Alkynes

Scheme 8. An Unusual Rh-Catalyzed [2+2+1] CrossCyclotrimerization After this pioneering work, many more reports of pentafulvene synthesis using Pd catalysis emerged. In 1991, Heck and coworkers published a palladium-catalyzed reaction of vinylic bromides with disubstituted alkynes 29 for the synthesis of penta- or hexa-substituted pentafulvenes 31 (Scheme 6a).67 Yamamoto and co-workers then extended this original transformation using terminal alkynes to yield pentafulvenes with three substitutions on the endocyclic ring.68 Earlier reports on the transition metal-catalyzed synthesis of pentafulvenes had some limitations, such as the need for elevated temperatures, moderate yields, and a lack of generality.67,69 Takahashi and coworkers overcame all of these constraints by developing a novel synthetic route to pentasubstituted pentafulvenes from two alkynes and an alkenyl iodide through palladium catalysis (Scheme 6b).70 It is interesting to note that, in addition to the palladium catalyst, the silver salt and carbonate ions significantly

Recently, an efficient gold-catalyzed intramolecular furan/yne cyclization reaction was developed to produce functionalized fulvenes 40 with enone or enal moieties under mild reaction conditions, with controllable E- or Z-stereoselectivity (Scheme 9).76 This reaction is considered as the first gold-catalyzed ringopening cyclization of furan/ynes with the shortest tether between furan and the alkyne moiety, via 6-endo cyclization. The 3935


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Scheme 9. Gold-Catalyzed Intramolecular Furan/yne Cyclization

3.3. Miscellaneous Reactions

nature of the solvent plays a significant role in controlling the Eor Z-stereochemistry of the double bond in the pentafulvene. 6,6-Dimethylfulvene 2 can be used as a precursor for vinyl cyclopentadienyl anion 41, which is highly reactive toward electrophiles. In 1991, Nyström et al. utilized this reactivity for the preparation of 7-substituted fulvenes 43 by palladiumcatalyzed reactions.77 Subsequently, they extended the scope of this methodology by employing substituted electrophiles (Scheme 10).78

Apart from the numerous synthetic methods discussed above, several original synthetic protocols have been developed for specifically substituted or highly functionalized pentafulvenes. 1,2,3,4-Tetramethylfulvene 44 is an important building block in organometallic chemistry (see section 6), and several syntheses have been reported (Scheme 11). Jutzi prepared this compound starting from pentamethylcyclopentadienyl bromide 45.79,80 Ogino and Erker obtained the compound by hydride abstraction from LiCp* using a trityl cation.81,82 Later, Krut’ko and coworkers investigated the formation of 44 from (trimethylsilyl) tetramethyl cyclopentadienide anion 47 by the reaction of formaldehyde through a combined experimental and theoretical study.83 Tetra- and penta-substituted pentafulvenes with interesting regioselectivity (1,2,3,6,6 and 1,2,6,6) were obtained by Cazes and co-workers through a two-step procedure starting from 4alkylidenecyclopentenones.84 Addition of an organometallic reagent or reduction with LiAlH4 followed by dehydration efficiently afforded the polysubstituted pentafulvenes. In 2003, Lee and co-workers developed a novel synthetic path toward 1,4,6-trisubstituted pentafulvenes 51 (Scheme 12), which served as precursors for the synthesis of new ansa-metallocene complexes for olefin (co)polymerizations.85 Swager and co-workers prepared 6,6-dicyanofulvenes (6, see section 2.1) from masked, dimeric, or monomeric cyclo-

Scheme 10. Preparation of 7-Substituted Fulvenes by Palladium-Catalyzed Reactions

Scheme 11. Overview of 1,2,3,4-Tetramethylfulvene Syntheses

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Scheme 12. Synthesis of 1,4,6-Substituted 6-Phenylfulvenes

Scheme 14. Synthesis of 1,3,6-Trisubstituted 6Aminofulvenes

Scheme 15. Synthesis of CF3-Substituted Fulvenes

pentadienones by reaction with dicyanomethane under acid catalysis.41 Later, a highly functionalized 6,6-dicyanopentafulvene 57 was prepared by solvent polarity controlled nonconcerted [2+2] cycloaddition between N,N-dimethylanilinosubstituted 1,1,2,4,4-pentacyanobuta-1,3-diene 52 and 4-ethynyl-N,N-dimethylaniline 53 (Scheme 13).86 In low-polarity solvents (toluene, DCM, THF), compounds 54 and 55 were the major products (ca. 2:1 ratio), whereas in DMF or acetonitrile, the major compound was the spirocyclic product 56. The formation of 57 from 54 involves a formal 1,5elimination of HCN under cyclization, which might follow a radical mechanism. A series of novel 1,3,6-substituted 6-aminofulvenes 60 were synthesized from inexpensive and readily available imines via a potassium hydride-mediated trimerization reaction (Scheme 14).87 Recently, an unusual transformation of cinnamils to 2,3,8triarylvinylfulvenes, mediated by N-heterocyclic carbenes (NHC), was developed by Nair and co-workers.88 The cyclofunctionalization of trifluoromethylated cyclopentadiene, generated by Nazarov-cyclization of diene 61, using Vilsmeier conditions and subsequent hydrolysis, generated the corresponding CF3-fulvenes 62 (Scheme 15).89 Very recently, an efficient protocol to access a variety of functionalized 6-hydroxyfulvenes 65 bearing two carbonyl groups was developed through a [3+2] annulation reaction (Scheme 16).90 The electronic properties of the aromatic substituents in compound 65 have a prominent influence on the yield of the reaction. This report offers an efficient and straightforward route to acidic multisubstituted pentafulvenes.

Scheme 16. Synthesis of Functionalized 6-Hydroxyfulvenes Bearing Two Carbonyl Groups

Later, an efficient and convenient method for the preparation of highly substituted pentafulvenes 70 carrying several functional groups was developed from 1,3-diketones 68 via a novel domino reaction using N-(4-trifluoromethylbenzyl)cinchonium bromide 69 as chiral phase-transfer catalyst, under mild reaction

Scheme 13. Preparation of 6,6-Dicyanofulvene by Nonconcerted [2+2] Cycloaddition

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Scheme 17. Domino Reaction for the Synthesis of Highly Substituted Fulvenes Using a Chiral Phase-Transfer Catalyst

conditions (Scheme 17).91 The reaction scope is large due to the formation of only the E-isomer. Despite the wide range of procedures expressed in this Review, the conventional methods established by Thiele, Little, and Erden are still considered the most common methods for the preparation of pentafulvenes.

exocyclic C6 position raise the HOMO sufficiently to induce reactions of fulvenes as trienes with electron-deficient 4π systems. Thus, alkyl- or arylfulvenes react as 2π dienophiles or dipolarophiles with most dienes and 1,3-dipoles, respectively. With electron-rich dienes, it is the fulvene LUMO that is concerned, and the large coefficients at C6 and C1 indicate that it will act as a 6π component. A wide range of cycloaddition reactions of pentafulvenes have been revealed by many groups, illustrating their versatility. For example, [2+2], [4+2], [2+4], [6+4], and [6+2] cycloadditions of pentafulvenes provide efficient and powerful approaches toward polycyclic systems and natural products. The aim of this section is to critically appraise the cycloaddition patterns of pentafulvenes, concentrating in particular on the advances that have been made in the period 1984−2016. In view of the volume and impact of the accessible literature, we have divided the entire topic into five sections.

4. CYCLOADDITION CHEMISTRY OF PENTAFULVENES Cycloaddition reactions occupy a conspicuous place in the toolbox of synthetic chemists and are among the most reliable of chemical transformations accessible to date.92 The fascinating chemistry manifested through these reactions provides sufficient confidence to synthetic chemists to take on challenging goals, often leading to spectacular results. The emergence of pentafulvenes as versatile scaffolds enormously expanded the scope of cycloaddition reactions, attributable to the multiple reaction profiles exhibited by them and the diversity of the reaction products. Pentafulvenes are able to act as 2π, 4π, or 6π candidates and have been recognized as the eminent building unit of many fused complex ring systems through intra- and intermolecular cycloaddition reactions. The substituents on the fulvene and the other substrate regulate the periselectivity of these reactions. Pentafulvenes behave as 2π components with electrondeficient dienes and as 6π components with electron-rich dienes. The deviation in the periselectivity of cycloadditions of fulvenes can be interpreted with help from frontier molecular orbital (FMO) theory. The orbital coefficients of the HOMO and LUMO of fulvene are depicted in Figure 3. The reactions of moderately electron-deficient 4π electron systems take place across the C1, C2 alkene moiety because of the high frontier density in these positions and the node through the exocyclic position. Only strong electron-donating substituents at the

4.1. Pentafulvene as 2π Components

Pentafulvenes behave as 2π components with electron-deficient dienes. According to the selection rules, a thermal [2+2] cycloaddition is not expected from pentafulvenes due to symmetry reasons. Interestingly, the reactivity of pentafulvenes with ketenes has developed into a general and powerful approach to the synthesis of various polycyclic systems. The reactions with ketenes are suprafacial-antarafacial and for that reason are thermally allowed. A striking example of this category of cycloaddition was revealed by the research group of Imafuku.93 The authors accomplished an efficient route to substituted tropolone derivatives 74 via a [2+2] cycloaddition between 2alkyl-6,6-dimethylfulvene 71 and dichloroketene 72, which is generated in situ from dichloroacetyl chloride (Scheme 18). Scheme 18. [2+2] Cycloaddition between 2-Alkyl-6,6dimethylfulvene and Dichloroketene

Chang and co-workers have adopted a similar protocol toward the total synthesis of iridoid natural products loganin 80 and sarracenin 81.94 The intermediate for both of the natural products was obtained from the versatile diquinane 78, which was afforded from the [2+2] cycloaddition reaction of 6-

Figure 3. Frontier molecular orbitals of fulvene. Reproduced (adapted) with permission from ref 2. Copyright 1989 John Wiley and Sons. 3938


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acetoxyfulvene 75 with the in situ generated methylchloroketene (Scheme 19).

Scheme 22. Reaction of Cyanobenzocyclobutene with Excess Dimethylfulvene

Scheme 19. Total Synthesis of Iridoid Natural Products Loganin and Sarracenin

To illustrate the unusual solvent effect on the cycloaddition mode of pentafulvenes, Yasunami et al. carried out a reaction between 6,6-dimethylfulvene and 3-methoxycarbonyl-2Hcyclohepta[b]furan-2-one 90.98 The reaction procedes either through a [4+2] or a [8+2] cycloaddition pathway, depending on the solvent. The [4+2] cycloadduct 91 was afforded as a major product in ethanol or benzene, together with minor [8+2] adduct 92, while the latter was formed exclusively in xylene (Scheme 23, R = Me). It was shown that the [4+2] cycloadduct could be transformed to the [8+2] cycloadduct in refluxing xylene by a retro−Diels−Alder reaction and a recycloaddition reaction, followed by spontaneous decarboxylation. Succeeding reports by Nair et al. have elaborated and generalized the above cycloaddition tactic for a number of 6,6-dialkyl-, -diaryl-, and -cycloalkylpentafulvenes, and rationalized the results with the aid of comprehensive theoretical calculations (Scheme 23, R = Et).99 Cycloaddition reactions of o-quinones have gained significant attention in organic synthesis due to the propensity of these compounds to function as carbodienes, heterodienes, and dienophiles.100 The reactivity of these substrates toward fulvenes was realized prior to 1980; however, the work remained limited to isolated efforts of Friedrichsen and co-workers.101,102 The studies in our laboratory have recognized that pentafulvenes perform as efficient 2π components with 1,2-benzoquinones, resulting in bicyclo[2.2.2]octen-7,8-dione adduct 94 in good to excellent yield from the reaction of 6,6-disubstituted fulvenes with substituted o-quinones 93 (Scheme 24).103 The reaction of o-quinone with cyclic fulvenes led to novel products 96, which arise due to the isomerization of the fulvene to cycloalk-1-enyl cyclopentadiene and subsequent cycloaddition of the latter with the quinone (Scheme 25). Continued investigations in this area have unraveled the reactivity of a sequence of symmetrical as well as unsymmetrical fulvenes with diverse 1,2-benzoquinones, ranging from simple methoxy-substituted examples to sterically demanding variants.104−111 In addition to these exciting results and the new insights gained from the cycloaddition reactions of pentafulvenes, the cycloadducts showed the potential for a number of interesting transformations. Adducts 94 undergo rapid double decarbonylation reactions upon photolysis, providing an efficient synthesis of highly substituted indene and benzene derivatives 98.112 The condensation of the adducts with 1,2-diamines smoothly afforded pyrazino barrelene derivatives 100, which

As mentioned earlier, pentafulvene displays different reactivity patterns with different cycloaddition partners. In the early 1970s, Houk et al. revealed that fulvene acted as a 4π component with the tetraene system of tropone, affording a double [6+4]-type adduct.95 In contrast to this unusual reactivity, Machiguchi et al. found that fulvene can act as a 2π component with tropothione 82, in which the latter serves as the 8π component (Scheme 20).96 Scheme 20. [8+2] Cycloaddition between Fulvene and Tropothione

The exocyclic double bond of pentafulvene is reluctant to participate as a 2π component. However, an exciting report on the cycloadditions of o-xylylenes to pentafulvenes came from Houk et al. This method showed that the electron-deficient oxylylenes react in a [4+2] manner with the endocyclic double bond of fulvene, whereas electron-rich o-xylylenes add primarily in the same fashion to the exocyclic double bond. The presence of electron-withdrawing substituents at the C6 position of fulvene further stimulates the exocyclic double bond in cycloaddition reactions. For example, the reaction of fulvene 11 with [(methoxycarbonyl)amino]benzocyclobutene 84 resulted in spiro adduct 85 (93% yield), which can be transformed to the benzoazulene 86 under basic conditions (Scheme 21).97 On the other hand, the reaction of cyanobenzocyclobutene 87 with excess dimethylfulvene 2 afforded a single [4+2] adduct 89 in 67% yield (Scheme 22).

Scheme 21. Reaction of Fulvene with [(Methoxycarbonyl)amino]benzocyclobutene

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Scheme 23. [4+2] or [8+2] Cycloaddition of Pentafulvenes with 3-Alkoxycarbonyl-2H-cyclohepta[b]furan-2-one

Scheme 24. Reaction of 6,6-Disubstituted Fulvenes with Substituted o-Quinones

thioquinone with pentafulvenes, resulting in the efficient synthesis of 1,4-benzoxathiins 103.114 It is noteworthy that fulvene participates as a 2π component and o-thioquinone 102 as a 4π heterodiene component. This contrasts with the reactivity of o-benzoquinones, which generally serve as carbodienes toward fulvenes (Scheme 27). Another hetero-Diels−Alder reaction reported by the same group consists of the reaction of pentafulvenes with coumarin quinone methide 105, leading to novel pyranocoumarin derivatives in good yield (Scheme 28).115 An interesting hetero-Diels−Alder reaction of pentafulvenes with tetracyclic cage compounds 108 was reported by Nair et al. (Scheme 29).116 As compared to their conventional counterparts, microwave reactions are faster, higher yielding, and retain the backbone structure of the thermal products.117 Hong et al. have succeeded in developing the use of microwave irradiation to change the reaction pathway for certain cycloadditions of fulvenes.118 For example, microwave-assisted cycloaddition reaction of 6,6-

Scheme 25. Reaction of o-Quinone with Cyclic Fulvenes

undergo di-π-methane rearrangement. Another useful transformation was the Lewis acid-catalyzed rearrangement of the bicyclo[2.2.2] adducts, leading to a simple entry into bicyclo[3.2.1] systems 99 (Scheme 26).113 By continuing their investigations along the same line, Nair et al. have uncovered the cycloaddition reaction of an o-

Scheme 26. Photolysis and Lewis Acid-Catalyzed Transformation of Bicyclo[2.2.2] Adducts

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Scheme 27. [4+2] Cycloaddition Reaction of an oThioquinone with Pentafulvenes

Scheme 29. Diels−Alder Reaction of Pentafulvenes with Tetracyclic Cage Compounds

Scheme 30. Microwave-Assisted [3+2] and Thermal [4+2] Cycloadditions of Fulvenes with Benzoquinone dimethylfulvene 2 and benzoquinone 110 afforded the hetero [3+2] adduct 111, which is a structural analogue of the natural products apylysin and pannellin. This differs markedly from the renowned thermal Diels−Alder cycloaddition products (112) of fulvenes and benzoquinone (Scheme 30).119 Similar chemistry with a series of homologous alkenes and alkynes has also been reported, resulting in the formation of intriguing polycyclic ring systems found in numerous natural products. The inverse electron demand Diels−Alder (IEDA) reaction of azadienes has attracted much attention in natural product synthesis.120 As an example, Hong and co-workers established an extremely regio- and stereoselective IEDA cycloaddition reaction of pentafulvenes with azadienes.121 The methodology offered an effective synthetic protocol toward [1]-pyrindine system 114. Similar trends in reactivity were found for a related series of pentafulvenes and azadienes (Scheme 31).

Scheme 31. Inverse Electron Demand Diels−Alder Cycloaddition of Pentafulvenes with Azadienes

4.2. Pentafulvenes as 4π Components

Scheme 32. Reaction of 6,6-Dimethylfulvene with Maleimide

Further, in reactions with numerous hetero and homodienes, pentafulvenes can perform as extremely reactive dienes, as is clear from the existing literature on the cycloaddition reactions concerning fulvenes and various dienophiles. The Diels−Alder cycloaddition of pentafulvenes with dienophiles such as maleimide and maleic anhydride has been the topic of many publications connected to supramolecular chemistry.122 By employing the simple Diels−Alder cycloaddition reaction between dimethylfulvene and maleimide, Deslongchamps et al. described the design and synthesis of a novel scaffold for molecular recognition.123 Maleimide 115 reacted with 6,6dimethylfulvene in refluxing toluene, affording [4+2] cycloadducts as an 8:1 mixture of exo and endo isomers. The major exo isomer 116 was readily converted to 117, which was used for the rapid assembly of abiotic receptors toward neutral organic guest molecules (Scheme 32). The simple structural unit, and the capability of the stiff carbobicyclic framework 117 to introduce the hydroxyl group cis to the latent imide group, made the protocol attractive for molecular recognition.

In contrast to simple dialkyl- or diarylfulvenes, 6-adamantylidenefulvene has not gained much attention in cycloaddition reactions. To address this problem, Warrener et al. conducted a reaction between 6-adamantylidenefulvene and a reactive dienophile, Smith’s diene 119, affording the [4+2] cycloadduct 120 in good yield.124 Here, the adamantyl group is rigidly bound to the molecular framework by the olefinic linkage originating from the fulvene (Scheme 33). This reaction has also been exploited for the development of bis-adducts by employing a modified Smith’s diene under high pressure conditions.

Scheme 28. Reaction of Pentafulvenes with Coumarin Quinone Methide

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norborno-5-enyl aldehydes and ketones 131 and 135 in good yields (Scheme 35). Muthusamy et al. developed an efficient and stereoselective protocol for the production of syn-facially bridged norbornane frameworks 138 from pentafulvene derivatives via reactions with rhodium carbenoids produced from diazo ketones 137 (Scheme 36).127 The intramolecular Diels−Alder (IMDA) reaction involving fulvenes as 4π components is a powerful strategy for the creation of polycyclic systems and has been effectively applied to the synthesis of various natural products.128 Raghunathan and coworkers have revealed an intramolecular [4+2] cycloaddition of fulvenes leading to 6-oxatricyclo[6.4.0.0]dodeca-2,11-diene ring systems, such as 140 (Scheme 37).129 Subsequently, they have extended this strategy to many substituted oxatricyclo ring systems and identified the steric features that promote this intramolecular cycloaddition reaction. Hatanaka and co-workers demonstrated an efficient synthesis, as well as highly regio- and stereoselective [4+2] cycloaddition reactions, of 4-((R)-3-benzyloxy-pent-4-en-1-yl)fulvene 141, including its transformation into bicyclo[3.3.0]octene 143 by mild acid treatment (Scheme 38).130 In 2006, Hong et al. established a highly regioselective electrophilic substitution of pentafulvene with ethyl glyoxylate 144, and then utilized this substituted pentafulvene for further Diels−Alder reactions with various dienophiles (Scheme 39).131 Recently, an IMDA concerning simple acyclic fulvene molecules was established by Hong and co-workers, leading to the synthesis of a variety of polycyclic skeletons present in pharmaceutical agents such as SP 18904, treprostinil, and kigelinol.132 An excellent example of this approach is shown in Scheme 40. They also pointed out that the length of the chain and the diversity of the substituents on the fulvene can dictate the nature of the cycloaddition pathway. In 2012, Biju and co-workers reported a high-yielding, versatile, and practical Diels−Alder reaction of pentafulvenes with arynes under mild reaction conditions.133 The arynes produced by the fluoride-mediated 1,2-elimination of 2(trimethylsilyl)aryl triflates 155 ensure efficient cycloaddition with 6-substituted and 6,6-disubstituted pentafulvenes, leading to the construction of benzonorbornadiene derivatives 156 and 157 (Scheme 41).

Scheme 33. Cycloaddition Reaction between 6Adamantylidenefulvene and Smith’s Diene

Pentafulvenes with extended conjugation offer multiple modes of cycloaddition reactions, including higher-order versions; however, such reactions have received only limited attention in organic synthesis. After their investigations involving pentafulvenes, Nair et al. observed two different reactivity patterns of 6(2-phenylethenyl)fulvene 121 in cycloaddition reactions with various electron-deficient dienophiles and dienes (Scheme 34).125 Theoretical calculations rationalized the participation of the fulvene both as a 4π and 2π component. Scheme 34. Reactivity Patterns of 6-(2-Phenylethenyl)fulvene with Various Electron-Deficient Dienophiles and Dienes

The Diels−Alder reactions of 6-silyloxyfulvenes 128 with various dienophiles, leading to 7-substituted bicyclo[2.2.1]hepta2,5-diene and hept-5-ene derivatives, were established by Jousseaume et al.126 Treatment of these adducts with n-Bu4NF resulted in the formation of 7-norborno-2,5-dienyl and 7-

Scheme 35. Diels−Alder Reactions of 6-Silyloxyfulvenes with Various Dienophiles

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Scheme 36. Construction of syn-Facially Bridged Norbornane Frameworks

Scheme 37. Intramolecular [4+2] Cycloaddition of Fulvenes for Oxatricyclo Ring Systems

Scheme 40. Intramolecular [4+2] Cycloaddition of a Simple Acyclic Fulvene

Scheme 38. Stereoselective [4+2] Cycloaddition Reaction of 4-[(R)-3-Benzyloxy-pent-4-en-1-yl)fulvene and Its Transformation into Bicyclo[3.3.0]octene

An efficient protocol to synthesize a spiropentacyclic motif with an indoline and pyrazolidine fused to cyclopentene was reported by Radhakrishnan and co-workers through a palladium/ Lewis acid-mediated domino reaction of pentafulvene derived diazabicyclic olefins.136 Very recently, an in situ generated unsubstituted pentafulvene was used as a precursor for the total synthesis of pallambins A and B, 164 and 165, via an unusual Diels−Alder reaction (Scheme 43).137 4.3. Pentafulvene as 6π Components

The pioneering work by Houk and co-workers established that pentafulvenes can also be utilized as 6π components in cycloaddition reactions. As a proof of concept, they have developed an efficient protocol for the synthesis of azulenes via the [6+4] cycloaddition of pentafulvenes and electron-rich aminobutadienes.138 For example, the cycloaddition of 6phenylfulvene with 1-diethylaminobutadiene 167, followed by the elimination of diethylamine, resulted in the hydrazulene derivative 168, which on reaction with chloranil afforded the phenyl substituted azulene 169 (Scheme 44). The same research group, in quick succession, developed an intramolecular version of the reaction by resorting to an

Subsequently, Qiu and co-workers reported the synthesis of carboranonorbornadienes in moderate yields with excellent regioselectivity from 6,6′-diarylfulvenes via [4+2] cycloaddition.134 This method is suitable for the synthesis of a new class of multiply functionalized o-carborane derivatives that may have potential applications in medicine and materials science. In 2014, Molchanov and co-workers reported a Lewis acid-catalyzed formal aza-Diels−Alder (Povarov) reaction involving fulvenes and aromatic imines 158 for the first time.135 However, the reaction was limited to only dimethylfulvene, and the yield was very low due to polymerization (Scheme 42).

Scheme 39. Highly Regioselective Electrophilic Substitution of Pentafulvene, Followed by Diels−Alder Reaction

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Scheme 41. Diels−Alder Reaction of Pentafulvenes with Arynes

In 1985, an alternative intramolecular variant of the reaction was reported by Houk and co-workers.140 They established a fascinating tricyclopentanoid synthesis with the development of an intramolecular [6+2] cycloaddition reaction of fulvenes with a pendant enamine group (Scheme 46). One year later, the same research group reported the intramolecular [8+6] cycloaddition reaction of a pentafulvene tethered heptafulvene framework 176, leading to the tetracyclic compound 177, in moderate yield (Scheme 47).141 In contrast to intramolecular cycloaddition reactions comprising higher-order π systems (vide supra), intermolecular versions suffer from the loss of regioselectivity, endo/exo selectivity, and diastereofacial selectivity. Liu and Ding contributed ample evidence for this idea by attempting the cycloadditions of pentafulvenes with the higher homologue of the fulvenoid family, heptafulvene 178.142 Multiple cycloaddition profiles were observed, and the reactions were affected by low yields and a lack of periselectivity, affording a mixture of [6+4], [8+2], and/or [4+2] adducts depending on the reaction conditions (Scheme 48). The in situ generated acetone pyrrolidine enamine 182 undergoes [6+2] cycloadditions with fulvenes to provide 1,2dihydropentalenes 183 (Scheme 49).143 This ring annulation method is predominantly successful with 6-monosubstituted fulvenes and is subject to steric hindrance at the C6 position of the fulvene. Through mechanistic studies, reaction conditions have been optimized for a one-pot synthesis of 1,2dihydropentalenes 183 by means of catalytic amounts of pyrrolidine. In the same year, Uchimaru and co-workers reported an organocatalytic, enantioselective intramolecular [6+2] cycloaddition reaction for the formation of tricyclopentanoids 185 (Scheme 50), and the experimental results were rationalized with theoretical studies.144 As mentioned earlier, to induce pentafulvene to react as a 6π component, either the cycloaddition partner or the pentafulvene itself must be electron-rich. Naturally, these restrictions limited the scope of this cycloaddition mode, and this is evident from the limited number of reports published over the last two decades. However, the recent enhancement observed in the chemistry of electron-rich fulvenes and metal-mediated cycloadditions, along with the launch of various electron-rich dipoles as partners, established the reactivity of pentafulvene as a 6π component and made the approach an efficient strategy for the construction of impressive organic structures. Accordingly, a number of significant reports on this cycloaddition cascade are available, as shown later in this Review.

Scheme 42. Lewis Acid-Catalyzed Formal Aza-Diels−Alder (Povarov) Reaction Involving Fulvenes and Aromatic Imines

Scheme 43. Total Synthesis of Pallambins A and B

Scheme 44. [6+4] Cycloaddition of Pentafulvenes and Electron-Rich Aminobutadienes

extremely selective intramolecular [6+4] cycloaddition of aminodienylfulvenes 170, leading to tricyclic systems 172 (Scheme 45).139 Scheme 45. Intramolecular [6+4] Cycloaddition of Aminodienylfulvenes

4.4. Pentafulvenes in Dipolar Cycloaddition Reactions

1,3-Dipolar addition offers a remarkably wide range of utility as a high-yielding, efficient, regio-, and stereocontrolled method for 3944


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Scheme 46. Intramolecular [6+2] Cycloaddition Reaction of Fulvenes with a Pendant Enamine Group

Scheme 47. Intramolecular [8+6] Cycloaddition Reaction of a Pentafulvene Tethered Heptafulvene Framework

Scheme 49. [6+2] Cycloadditions of Acetone Pyrrolidine Enamine with Fulvenes

the synthesis of numerous carbocyclic and heterocyclic compounds.145 The dipolar family always inspired the search and combination of versatile dipolarophiles for executing superior chemistry. In view of the potential features achievable through the chemistry of pentafulvenes, there was general acceptance for them in the zone of dipolar cycloaddition reactions. This segment delivers an overview of the available literature on this topic of organic chemistry, with emphasis on the recent accomplishments in our laboratory. Mesoionic ring systems are well-known 1,3-dipolar species and are employed as synthons for a variety of heterocycles.146 Kato and co-workers were the first to advance the dipolar chemistry of pentafulvenes with mesoionic compounds. Numerous mesoionic compounds have been reacted with pentafulvene derivatives to form [4+2] and [4+6] cycloadducts, which under the reaction conditions undergo fragmentation, elimination, or isomerization, leading to a variety of heterocycles isoelectronic with azulene. The reaction of 3-phenylsydnone 187 with 2-tert-butyl-6,6dimethylfulvene 186 afforded the condensed pyrazole 188 by ejection of carbon dioxide from the originally formed [4+2] cycloadduct, followed by spontaneous dehydrogenation (Scheme 51).147 Nair et al. established the first dipolar cycloaddition reaction of conjugated pentafulvenes. They revealed that 6-(2phenylethenyl)fulvene 121 underwent quick reaction with various aryl nitrile oxides 189, leading to isooxazoline derivatives 190 (Scheme 52).148 Here, the fulvene participates as a 2π cycloaddition partner, and the periselectivity of the reaction was rationalized by theoretical calculations. Cyclodextrins (CD),149 because of their inclusion ability, have become one of the archetypal host systems for organic compounds, and have been exploited to enhance the reaction

rate and selectivity of several useful transformations, including cycloaddition reactions. Chung and co-workers have achieved a CD modulated, highly regio- and stereoselective dipolar cycloaddition reaction of 6-adamantylidenefulvene with various nitrile oxides using both thermal and microwave irradiation (Scheme 53).150 Except for a few isolated and unclear literature reports, the dipolar reactivity of diphenylnitrilimine with pentafulvenes was not studied prior to 2000.151 In early 2000, Ciamala et al. have demonstrated the [3+2] dipolar cycloaddition reactions of diphenylpentafulvene with various diarylnitrilimines 194, leading to regioisomeric pyrazoline derivatives.152 They have also given the details of the acid promoted intramolecular rearrangement of the cycloadducts into substituted quinoline and pyrazole derivatives (Scheme 54). As a unique track toward oxatetracyclo[6.5.1.0.0]tetradecanes, Muthusamy et al. have established a facile [3+2] dipolar cycloaddition of rhodium generated carbonyl ylides with pentafulvenes.153 The 1,3-dipole obtained from the α-diazo carbonyl compound 200 on reaction with 6,6-dialkylfulvenes provided the cycloadducts 201a and 201b as a separable mixture of regioisomers (Scheme 55). A solitary report on the reactivity of a conjugated pentafulvene acting as a 10π component in a symmetry-allowed [10+4] dipolar cycloaddition reaction was reported by Warrener et al.154 The 1,3-dipolar precursor 203 trapped the 6,6-dimethylisobenzofulvene 202, affording the complex framework 204 (Scheme 56).

Scheme 48. Multiple Cycloaddition Profiles Shown by the Reaction of Pentafulvenes with Their Higher Homologue, a Heptafulvene

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Scheme 50. Enantioselective Intramolecular [6+2] Cycloaddition Reactions

The first catalytic enantioselective [6+3] cycloaddition of azomethine ylides 212 with fulvenes was reported by Waldmann and co-workers in 2012.159 Under the optimized conditions using a Cu+ salt and ferrocene-based ligand 216, the endopiperidine derivative 213a, with four stereocenters, was obtained as major product with high enantioselectivity. The reaction scope was extended by incorporating a [4+2] cycloaddition in a onepot procedure to obtain complex annulated piperidines 215 with eight stereocenters (Scheme 60). In a subsequent paper, the same group was able to furnish a highly diastereo- and enantioselective exo [6+3] cycloaddition of azomethine ylides to unsymmetrical fulvenes through a switch from ferrocenebased ligands to the (R)-difluorophos ligand 217.160 Wang and co-workers described a novel asymmetric [6+3] cycloaddition of imino esters with numerous easily accessible fulvenes, catalyzed by CuI/TF-Biphamphos under mild reaction conditions with good yields, excellent diastereoselectivities, high enantioselectivities, and broad substrate scope (Scheme 61).161 This methodology and subsequent transformations open new prospects for the straightforward synthesis of stereochemically rich piperidines 218, an important structural motif for drug discovery. Very recently, the same authors demonstrated that fulvenes without electron-withdrawing groups can act as 6π dipolarophiles in 1,3-dipolar [6+3] cycloaddition reactions with azomethine ylides.162 We have observed a simple but efficient [6+3] cycloaddition reaction of pentafulvenes with 3-oxidopyrylium betaines 220, and found that the approach presented a beneficial protocol for the synthesis of 5−8 fused cyclooctanoids 221 and 222 (Scheme 62).163 Similar chemistry was effectively prolonged to a number

Scheme 51. Reaction of 3-Phenylsydnone with 2-tert-Butyl6,6-dimethylfulvene

In an independent study, Chandrasekhar et al. reported the cycloaddition reaction of a single pentafulvene with diphenylnitrone.155 In 2002, Ciamala and co-workers offered a more extensive account of the cycloaddition between the two substrates.156 They exploited a series of mono- and disubstituted pentafulvenes with various aroylnitrones 205 and carried out detailed theoretical calculations that rationalized the formation of a mixture of regioisomers in good yields (Scheme 57). Hong et al. disclosed a significant effort that makes use of the pentafulvene-1,3-dipolar combination. In 2003, they established the [6+3] cycloaddition reaction of azomethine ylides made from glycine-N-benzylidene alkyl ester 207 with a series of pentafulvenes, affording biologically relevant [2]pyrindine systems 208 (Scheme 58).157 One year later, the same group uncovered the dual reactivity of pentafulvenes with 2H-azirine under a range of different conditions.158 In the presence of a Lewis acid, 2H-azirine 209 reacted with fulvenes via a formal regioselective [6+3] cycloaddition reaction and implemented an alternative, efficient synthesis of [2]pyrindine derivatives 210. In contrast, under ultrasound conditions, the reaction afforded alkylated fulvene azirines 211 through an unexpected rearrangement of the initial Diels−Alder cycloadduct (Scheme 59).

Scheme 52. Dipolar Cycloaddition Reaction of Conjugated Pentafulvenes with Aryl Nitrile Oxides

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Scheme 53. Dipolar Cycloaddition Reaction of 6-Adamantylidenefulvene with Nitrile Oxides

Scheme 54. [3+2] Dipolar Cycloaddition Reactions of Diphenylpentafulvene with Diarylnitrilimines

Scheme 55. Rhodium-Catalyzed [3+2] Dipolar Cycloaddition of Carbonyl Ylides with Pentafulvenes

Theoretical calculations were carried out to rationalize the results obtained; the studies have demonstrated an extremely stereospecific endo cycloaddition and a subsequent 1,5-H shift leading to the observed product.164 The direct formation of 5−8 fused cyclooctanoids via pentafulvenes is unique in cycloaddition chemistry, as the mild conditions and good yield augur well for further use of this methodology. Also, stimulated by the auspicious structural features accessible by these cycloadducts, we explored their synthetic utility in the construction of more complex but valuable polycyclic molecules. The carbon framework of the molecules was successfully extended through Diels−Alder reaction, dipolar cycloaddition, Luche reduction, selective hydrogenation, and others. These modifications led to oxa-bridged cyclooctanoids having an outstanding synthetic value, as these can act as key intermediates in the synthesis of various biologically relevant molecular frameworks (Scheme 63).165−167 By utilizing the cycloaddition potential of pentafulvenes, and at the same time as a notable continuation of our strategy, we developed an efficient spiroannulation reaction that allowed the effective synthesis of a variety of spirocyclic eight-membered rings 232 and 233 (Scheme 64).168 In conjunction with our continuous investigations, we found that the introduction of a pentafulvene with a bulky exocyclic

Scheme 56. [10+4] Dipolar Cycloaddition Reaction of 6,6Dimethylisobenzofulvene

Scheme 57. [3+2] Cycloaddition between Pentafulvenes and Aroylnitrones

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Scheme 58. [6+3] Cycloaddition Reactions of Azomethine Ylides with Pentafulvene

Scheme 59. Dual Reactivity of Pentafulvenes with 2H-Azirine

participation as 6π components. This statement was exemplified by the cycloaddition reactions of 6-(N,N-dimethylamino)fulvene and fulvene ketene acetal. Although the synthesis of these pentafulvenes was reported in the early 1970s,175,176 their chemistry was later expanded significantly by the efforts of Hong and co-workers. The first report on the cycloaddition reaction of activated pentafulvenes was disclosed by Kanematsu, who exposed 6,6dimethylaminofulvene to 2-oxyallyl cations 247, leading to the observation of [6+3] cycloaddition product 249, albeit in low yields.177 Earlier, Kashman et al. showed that the reaction of 6mono- and 6,6-dialkylfulvenes with 2-oxyallyl cations occurs through a [4+3] cycloaddition pathway.178 In 1996, Hong et al. subjected fulvene ketene acetal 251, having higher electron density than aminofulvene, to cycloaddition reactions.179 In this case, the reaction provided [6+3] adducts 252 in excellent yields, offering an efficient synthesis of highly substituted indene systems (Scheme 69). Later, the same research group extended the above protocol with synthetic transformations of the cycloadducts.180 Houk et al. were among the first to address the Diels−Alder cycloaddition between alkyl fulvenes and α-pyrone 254, an electron-deficient diene, to afford 255.181 In contrast to this observation, Hong et al. formulated an extremely proficient [6+4] cycloaddition of fulveneketene acetal with the same substrate (Scheme 70).182 This method offers an experimental framework and a theoretically novel tactic to prepare azulenols 257. 6-Aminofulvene also reacts with α-pyrones in a similar manner to give azulenes, albeit in low yields.183 Subsequently, a high yielding protocol employing microwave conditions was established.184 The microwave-assisted [6+4] cycloaddition reaction between 6-dimethylaminofulvenes and indole annulated pyrones 258 offered a smooth and efficient access to azulene-indoles 259 with stimulating antineoplastic activity (Scheme 71). Another fascinating reactivity profile of activated fulvenes was disclosed in 1999. Usually, pentafulvenes react as a 2π component with benzoquinones, affording [4+2] cycloadducts. In contrast, Hong et al. established a novel [6+3] cycloaddition reaction of 6-dimethylaminofulvene to benzoquinones 260, and

substituent had a marked effect on its reaction with 3oxidopyrylium betaine.169 This was exemplified by the cycloaddition reaction of 6-adamantylidenefulvene, which afforded [6+3] adduct 234 and novel [3+2] adduct 235 (Scheme 65). Inspired by the versatile cycloaddition profile of pentafulvenes with 3-oxidopyrylium betaines, our group recently undertook the cycloaddition of pentafulvenes with 3-oxidopyridinium betaines, afforded either by the action of a base on the pyridinium salt or thermally from pyridinium betaine dimer.170 The methodology furnished an extremely versatile approach toward the synthesis of bicyclo[6.3.0]undecanes 238 and bicyclo[5.3.0]decanes 239 via [6+3] and [3+2] cycloaddition reactions of pentafulvenes with 3oxidopyridinium betaines 236 (Scheme 66). A survey of the literature revealed that there are only limited data available on the reaction of 1,2,4-triazoline-3,5-dione with fulvenes.171 Apart from these exciting results, we developed a strategy toward highly functionalized azapolycycles involving pentafulvenes and N-phenyl-1,2,4-triazoline-3,5-diones 240 (Scheme 67).172 The observed reactivity was elucidated on the basis of the electronic and frontier molecular features of pentafulvene and triazolinedione. The addition of heterodienophiles 243 to fulvenes provides an efficient protocol toward the synthesis of azabicyclic olefins 244.173 However, there have been no deliberate efforts to study the synthetic utility of these substrates. In this context, we investigated the palladium/Lewis acid-catalyzed reaction of fulvene derived bicyclic hydrazines with various organostannanes.174 The reaction afforded substituted alkylidene cyclopentene 246 in excellent yield (Scheme 68). Alkylidene cyclopentenes are critical intermediates in the synthesis of some biologically active molecules, including (+) and (−)-nigellamine A2. 4.5. Cycloadditions of 6-Dimethylaminofulvenes and Fulvene Ketene Acetals

The alteration of the electron density at the exocyclic position of pentafulvenes has a perceptible effect on their reactivity. According to FMO theory, electron-donating substituents with substantial coefficients at the exocyclic position of fulvenes sufficiently raise the energy of the HOMO and trigger their 3948


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Scheme 60. Enantioselective endo or exo [6+3] Cycloaddition of Azomethine Ylides to Unsymmetrical Fulvenes

Scheme 61. CuI/TF-Biphamphos-Catalyzed Asymmetric [6+3] Cycloaddition of Imino Esters with Fulvenes

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relevant cyclopenta[d][1,2]oxazines 268 via a [6+4] cycloaddition between aminofulvenes and nitrile oxides (Scheme 75). Later, the same group established an efficient one-pot methodology to access cyclopenta[d]pyridazine 271 under mild conditions through the 1,3-dipolar cycloaddition of a fulvene and nitrile imine 269 (Scheme 76).191

Scheme 62. [6+3] Cycloaddition Reaction of Pentafulvenes with 3-Oxidopyrylium Betaines

5. MISCELLANEOUS REACTIONS OF PENTAFULVENES 5.1. Epoxidation of Fulvenes

In 1991, Adam et al. showed that dimethyldioxirane 272 can be used as a convenient and efficient oxygen transfer agent for the epoxidation of 6,6-disubstituted pentafulvenes.192 Here, the authors utilized the electrophilic nature of dimethyldioxirane as an oxidant (Scheme 77). Because the endocyclic double bonds are more electron-rich than exocyclic ones, the epoxidation occurred exclusively at the endocyclic position.

the reaction delivered a series of cyclopenta[c]chromene derivatives 262 that form the basic core of biologically active 11-oxasteroids (Scheme 72).185 Subsequently, the authors devised an efficient solid-phase version of the above transformation for the production of libraries of compounds.186 By further inspection, the same research group has revealed an uncommon but effective [6+2] cycloaddition reaction of 6aminofulvene.187 For example, the reaction of aminofulvene with maleic anhydride resulted in pentaleno[1,2-c]furan skeleton 263, which constitutes the basic skeleton of many natural products, such as anislactone A, merrilactone A, etc. (Scheme 73). Apart from the work of Hong et al., a significant contribution came from Leaver and co-workers. The authors have reported a short synthesis of azulenes 266 through a [6+4] cycloaddition of 6-dimethylaminofulvene with electron-deficient thiophene-1,1dioxide 264, followed by the spontaneous [4+2] cycloreversion to the intermediate cycloadduct 265 (Scheme 74).188,189 The suitable evidence on the cycloaddition chemistry of activated pentafulvenes came from Cho and co-workers.190 The authors have revealed an appropriate synthesis of biologically

5.2. Transformations of 6,6-Dicyanofulvenes: Isomerization to Benzene and [2+2] Cycloaddition−Retroelectrocyclization Reactions

A comprehensive report on the history and applications of dicyanofulvenes has recently been published by Diederich et al.;193 thus only a short overview on this chemistry will be given here. The reaction of a 3,5-bis(N,N-dimethylanilino)-substituted 2,4,6,6-tetracyanopentafulvene (TCPF) with mono- and bis(N,N-dimethylanilino) acetylenes was reported by this group in 2012. This methodology provides simple access to push−pull chromophores with diverse scaffolds, which show strong electronic absorption bands covering the entire visible spectral range into the near IR, and small HOMO−LUMO gaps.194,195 These properties, in line with high thermal stability and excellent solubility, made these new chromophores an excellent choice for use in molecular electronic devices. Later, the scope of 6,6dicyanopentafulvenes was exploited by preparing new fulvene-

Scheme 63. Synthetic Utility of 5-8 Fused Cyclooctanoids

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Scheme 64. Spiroannulation Reaction for the Synthesis of a Variety of Spirocyclic Eight-Membered Rings

FLP trans-1-[B(C6F5)2]-2-[CH2CH2PMes2]-disubstituted fulvene derivatives 284 (Scheme 80).206 This chemistry was further modified by an effective utilization of aminofulvene as a carbon-based Lewis base component in FLP generation. This pair can be effectively utilized for creating new carbon−carbon bonds with an alkyne substrate (Scheme 81).207 Recently, an independent study regarding an FLP was established by Paradies et al. using it as a catalyst for the hydrosilylation of pentafulvene. Here, the FLP not only acts as a catalyst but also suppresses the oligomerization of fulvenes. Dimethyl derivatives experience FLP-catalyzed hydrogenation followed by an unprecedented protodesilylation, resulting in isopropyl cyclopentene 288, while phenyl-substituted allyl silanes undergo B(C6F5)3-mediated rearrangement to vinyl silanes 291 (Scheme 82).208

Scheme 65. [6+3] and [3+2] Cycloaddition of 6Adamantylidenefulvene with 3-Oxidopyrylium Betaine

based push−pull chromophores via a formal [2+2] cycloaddition retroelectrocyclization reaction.196 The first thermal rearrangement of 6,6-dicyanopentafulvenes 276 to 1,3-dicyanobenzene 277 via a “ring-walk” mechanism (Scheme 78) was reported by the same group very recently.197

5.4. Hydroheteroarylation of Pentafulvenes

Hydroheteroarylation is one of the most prominent reactions in the arsenal of organic transformation. In particular, these are used for the functionalization of activated and unactivated olefins. A wide range of transition metals were used for this purpose.209−215 Very recently, our group established an exceptional strategy toward the regioselective hydroheteroarylation of pentafulvenes with various indoles 292 and pyrrole in the presence of a Lewis acid (Scheme 83).216 This protocol does not need dry solvents or inert atmospheres, and readily occurs at ambient temperature. This is the first report on the endo selective 1,2-addition of a nucleophile to fulvene catalyzed by a Lewis acid.

5.3. Frustrated Lewis Pair (FLP) Chemistry of Pentafulvenes

Frustrated Lewis pairs (FLP) are usually formed by the combination of coexisting Lewis acids and bases.198−201 Generally, a boron species serves as the Lewis acid, whereas phosphines or in rare cases N-heterocyclic carbenes can function as the Lewis base.202−204 Excess 6,6-dimethylpentafulvene reacts with the frustrated Lewis pair Mes2P−CH2CH2−B(C6F5)2 279 to produce P/B-Lewis pair addition product 280, which further transforms upon heating to elusive pentafulvene [6+4] cycloaddition dimer 282.205 This type of reactivity may open an innovative arena of frustrated Lewis pair chemistry (Scheme 79). The scope of this methodology was further extended in a subsequent report by the reaction of 6-dimethylamino-6methylfulvene with various diphenylalkylboranes, yielding the

5.5. Oxidative Addition of Pentafulvene

Generally, fulvenes undergo [2+2] cycloaddition with αchloroketene.217−219 In contrast, an independent study conducted by Hong et al. showed that by treating α-haloacyl halide

Scheme 66. [6+3] and [3+2] Cycloaddition Reactions of Pentafulvenes with 3-Oxidopyridinium Betaines

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Scheme 67. Reaction of 1,2,4-Triazoline-3,5-dione with Fulvenes

Scheme 68. Synthesis of Alkylidenecyclopentenes from Pentafulvene

Scheme 69. Reaction of 6,6-Dimethylaminofulvene and Fulvene Ketene Acetal with 2-Oxyallyl Cations

Scheme 70. Diels−Alder Cycloaddition between Alkylfulvenes and α-Pyrone

Scheme 71. [6+4] Cycloaddition Reaction between 6Dimethylaminofulvenes and Indole Annulated Pyrones

Scheme 72. [6+3] Cycloaddition Reaction of 6Dimethylaminofulvene and Benzoquinones

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Scheme 73. Reaction of Aminofulvene with Maleic Anhydride or Maleimide

Scheme 77. Epoxidation of Fulvenes by Dimethyldioxirane

Scheme 74. [6+4] Cycloaddition of 6-Dimethylaminofulvene with Thiophene-1,1-dioxide Hafner et al. explored the high potential of several “unusual” classes of fulvenes as building blocks in the chemistry of πelectron systems.223 Some of the compounds shown in Figure 4 may be appropriate for further transformation into molecules with promising chemical and physical properties. Later, the same group reported the synthesis of 2-(11,31-di-tertbutyl-pentafulven-61-yl)-tropone 311 by reaction of 6-lithio-1,3di-tert-butylpentafulvene 309 with 2-chlorotropone 310. At elevated temperatures, 311 cyclizes to form a mixture of the tautomeric azulene derivatives 312 and 313. With P2S5, 311 is transformed into the spiroadduct 315, presumably via the pentafulvenyltropothione 314. Compound 314 reacts by a thermally induced rearrangement to the stable cycloheptathialene derivative 317 (Scheme 86).224

Scheme 75. [6+4] Cycloaddition between Aminofulvenes and Nitrile Oxides

6. PENTAFULVENES IN METALLOCENE CHEMISTRY Fulvenes are not only excellent probes for cycloaddition reactions or interesting models for aromaticity studies and photophysical investigations. They have also found manifold applications in organometallic chemistry, either as easy-to-handle precursors for a large variety of the ubiquitous cyclopentadienyl ligands or as versatile ligands for a variety of transition metal complexes, providing numerous coordination modes and reactivity patterns. Furthermore, fulvenes are interesting substrates for organic transformations using organometallic reagents. This section will highlight important applications of pentafulvenes in organometallic chemistry over the last 25 years. Some aspects have been covered in previous reviews,225−230 in which case only the most recent results will be presented.

296 with 6,6-dialkoxyfulvene 251 in the presence of trimethylamine, a unique oxidative addition occurred, affording C1substituted fulvenes 299 via reactive acylated intermediates (Scheme 84).220 5.6. Chiral Pentafulvene as Brønsted Acid Catalyst in Organic Transformations

Very recently, Lambert and co-workers reported the synthesis of a chiral fulvene-based Brønsted acid 300, prepared in one step from naturally occurring (−)-menthol and readily available 1,2,3,4,5-pentacarbomethoxycyclopentadiene in the presence of N-methylimidazole in toluene.221 Fulvene 300 can be utilized as a catalyst for both Mukaiyama−Mannich and oxocarbenium aldol reactions with high efficiency and enantioselectivity (Scheme 85). The key factor contributing to this acidity is aromatic stabilization.

6.1. Pentafulvenes as Precursors for Cp ligands

The dipolar character of the exocyclic double bond in pentafulvenes makes the exocyclic carbon prone to nucleophilic attack (see section 2.2). The following sections will describe the addition of hydride, carbon, nitrogen, and phosphorus nucleophiles onto pentafulvenes, giving access to a wide range of sandwich and half-sandwich complexes with a broad range of applications in polymerization catalysis, organic chemistry, and medicinal chemistry. 6.1.1. Reductive Complexation. The formation of lithium cyclopentadienyl reagents obtained from the reduction of fulvenes with LiAlH4 has been known for a long time.14,15 Even though this approach was mainly used for the preparation of cyclopentadienes after workup, some transmetalation

5.7. Other Reactions

Junek et al. conducted an independent study concerning the reactivity of 1,2,3,4-tetrachloropentafulvene-6,6-dicarbonitrile toward anilines.222 These reactions led to the substitution of one or two chloro atoms and consequently a broad variation of the absorption spectra.

Scheme 76. 1,3-Dipolar Cycloaddition of a Fulvene and a Nitrileimine

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Scheme 78. Isomerization of 6,6-Dicyanopentafulvenes to Benzenes

unsymmetrically 6,6-disubstituted fulvenes allowed the synthesis of diastereomerically pure zirconocene complexes for polymerization catalysis after transmetalation and fractional crystallization. Mg(nBu)2 was shown to react in a similar fashion to lithium alkyl reagents; that is, the reaction with dicyclopropylfulvene provided the magnesocene Mg(C5H4CH(c-C3H5)2)2.235 More recently, the powerful superhydride reagent LiBEt3H has been widely applied to a large variety of 6-arylfulvenes. This method readily gives access to the corresponding lithium cyclopentadienyl precursors for direct use in the synthesis of titanocene,236−246 zirconocene,247 vanadocene,248−250 niobocene,251 molybdocene,252 and tin253 complexes (Scheme 87). Fulvenes with different electronic, steric, and solubility properties have been employed. Many of these metallocene complexes have been evaluated for their biological activity, exhibiting antiproliferative activity with several cancer cell lines. In 4f and 5f element chemistry, the reaction of samarium, yttrium, and uranium hydride precursors with 1,2,3,4-tetramethylfulvene has allowed the straightforward synthesis of otherwise difficult to access MCp*3 (M = Sm, Y, U) complexes 321.254−256 In the case of lanthanides, these complexes are known to exhibit unusual reduction chemistry, termed “sterically induced reductions”, despite the formal trivalent oxidation state of the metal.257 In the case of the smallest metal of the lanthanide series, lutetium, the reaction does not furnish the LuCp*3 complex but a rare lanthanide-vinyl complex 322 (Scheme 88).258 In situ generated zirconium hydride from Zr(nBu)2Cl2 reacts with fulvenes to afford the corresponding zirconocene dichloride complexes, which were successfully employed as ethylene polymerization catalysts.259 Depending on the reaction conditions, Zr(nBu)2Cl2 can also lead to reductive dimerization as a competing pathway. Monocyclopentadienyl complexes of group

Scheme 79. Reaction of 6,6-Dimethylpentafulvene with the Frustrated Lewis Pair Mes2P−CH2CH2−B(C6F5)2

Scheme 80. Reaction of FLPs with 6-Dimethylamino-6methylfulvene

reactions with FeCl2 or ReBr(CO)3 were also reported.231,232 Primary lithium alkyl reagents (n-BuLi, i-BuLi) have also been successfully employed for the reduction of fulvenes.233,234 This transformation was proposed to proceed via a β-hydride mechanism. The LiCp salts resulting from the reduction of

Scheme 81. Utilization of Aminofulvene as a Carbon-Based Lewis Base Component in Frustrated Lewis Pair Generation

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Scheme 82. Frustrated Lewis Pair-Catalyzed Hydrosilylation and Hydrosilane-Mediated Hydrogenation of Pentafulvenes

Scheme 83. Hydroheteroarylation of Pentafulvenes with Indoles

Scheme 84. Oxidative Addition of an α-Haloacyl Halide with a 6,6-Dialkoxyfulvene

reaction mixture. To investigate the synthetic applicability of this approach, the monomeric, nitrogen-base stabilized organotinhydride complex 326 was trapped with tetramethylfulvene. The reaction occurred instantly to yield the corresponding bright yellow Cp*Sn complex 329. In contrast, the reaction with the dimeric analogue does not proceed, unless pyridine or DMAP is added (Scheme 90).264 An enantiopure ruthenocene complex 331 could be obtained from the chiral (S)-2-(methoxymethyl)pyrrolidino derived fulvene 330 by salt metathesis after reduction with NaBEt3H (Scheme 91).265 Attempted reduction of the fulvene with LiAlH4

8 metals have been successfully applied in homogeneous catalysis.260,261 To widen the diversity of such complexes, the group of Jia has shown that a wide range of osmium262 and ruthenium263 half sandwich complexes 325 are available through the reaction of hydride precursors 323 and 324 with 6substituted fulvenes, via reductive complexation (Scheme 89). In the case of osmium, pyrene appended fulvenes as well as pentasubstituted fulvenes were successfully employed. During the study of the dehydrogenation of Ar*SnH3 induced by pyridine bases, a mixture of compounds 326−328 was obtained, depending on the amount of DMAP present in the 3955


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Scheme 85. Brønsted Acid Catalysis with a Chiral Pentafulvene

Scheme 87. Synthesis of Titanocene Dichloride Complexes by Reduction of 6-Arylfulvenes Followed by Transmetallation

Figure 4. 6-Halopentafulvenes, pentafulvenoid allenes, and pentafulvenoid ketenes.

The reaction of rhodium chloride with silylated fulvene 36 in ethanol was proposed to proceed via a Rh−H intermediate to finally yield the dinuclear electron-deficient cyclopentadienyl rhodium(III) complex 332. The resulting Rh(III) complex is a highly selective precatalyst for the oxidative coupling of acetanilides and alkynes (Scheme 92).75

led mainly to the substitution of the amine group to yield Li(C5H4Me).

Scheme 86. Reaction of 6-Lithio-1,3-di-tert-butylpentafulvene with 2-Chlorotropone

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new chiral zirconocene dichloride complexes, which were investigated for ethylene and propylene polymerization.279 The diastereoselective addition of lithium reagents onto chiral 6-dialkylaminofulvenes allowed the synthesis of chiral homo- or heteroleptic ferrocene complexes after transmetalation.280 A chiral hybrid Cp/scorpionate ligand 340 was obtained from the reaction of enantiopure (−)myrtenal derived fulvene 339 with lithium bis(3,5-dimethylpyrazol-1-yl)methide in 63% yield and with an excellent diastereomeric excess (>99% de) (Scheme 94). Reaction with diethylzinc furnished enantiopure zinc complex 341, which is the first complex capable of producing isotacticenriched poly(lactides) (Pi = 0.77) from rac-LA.281 A different approach was employed by Hayashi to access chiral rhodium and iron complexes. The addition of aryllithium reagents onto dimethylaminofulvene in the presence of chiral ligands (sparteine, box, diether) yielded the LiCp with up to 90% ee. Transmetalation with Rh(nor)Cl or FeCl2 yielded the corresponding chiral complexes (Scheme 95).282 These complexes are potential precursors for different types of chiral ferrocene derivatives through diastereoselective ortholithiation. The Cp* ligand has found widespread use in organometallic chemistry for its improved solubility and increased steric bulk as compared to the unsubstituted Cp ligand. Hybrid Cp* ligands can be readily accessed by the reaction of lithium reagents with 1,2,3,4-tetramethylfulvene. Addition of Li-carbazolyl onto 1,2,3,4-tetramethylfulvene provided a new Cp* ligand that gave highly luminescent Tb3+ complexes.283 Similarly, a naphthyl group could be introduced in the Cp* ligand, giving access to a new divalent samarium complex.284 Addition of lithiated methylpyridine derivatives onto 1,2,3,4-tetramethylfulvene afforded mono or bis-Cp*-pyridine ligands, which were readily coordinated to iron.285 Cp*/NHC ligand precursors 344 were isolated from the reaction of 1,2,3,4-tetramethylfulvene with NHC-benzyl precursor 343 (Scheme 96). Ir, Rh, and Ni complexes could be obtained and employed in catalysis, for example, in the dehydrogenative coupling of aromatic thiols with Et3SiH.286,287 The addition of Grignard reagents to fulvenes is less common than organolithium reagents. A remarkable example is coppercatalyzed addition of various alkyl or aryl Grignard reagents to 6(2-methoxyphenyl)fulvene (Scheme 97).288 As pointed out in the previous section, alkyl magnesium reagents can readily furnish the hydride product. However, in this case, good yields of the alkylated Cp product 347 were obtained. Even rarer is the copper-catalyzed addition of ZnEt2 onto the exocyclic double bond. With chiral phosphoamidate ligands, an er of up to 90:10 could be reached. Addition of the phosphoric acid derivative had an important effect on the rate of carbozincation. The 6-aryl unit has a crucial influence on the reaction outcome: the presence of a coordinating group close to

Scheme 88. Reactions of [LnCp*2(μ-H)]2 (Ln = Sm, Y, Lu) with Tetramethylfulvene

6.1.2. Carbometalation Reactions. The addition of organometallic reagents onto the exocyclic double bond of fulvenes readily gives access to diversely substituted cyclopentadienyl metal precursors that can be further employed in salt metathesis reactions. Tacke reported several titanocene complexes resulting from the reaction of 6-arylfulvenes with aryllithium reagents and transmetalation with TiCl4.225 Importantly, the aryl groups were kept identical so as not to create a chiral environment. Alternatively, 6,6-bis(dimethylamino)-substituted fulvene was reacted with lithiated heterocycles. The same group also investigated the addition of various aryllithium reagents onto 6-dimethylaminofulvenes, leading to mixtures of chiral titanocene complexes after transmetalation. These complexes exhibited high cytotoxicity, which may arise from the stabilization of mono- or dications through intramolecular coordination from the N,N-dimethylamino groups.225 Jaouen used this approach for the synthesis of Cp ligands containing steroid groups, which were employed for the synthesis of nonradioactive Re complexes.231 The addition of Li-indenyl or -fluorenyl compounds onto fulvenes has been developed as a straightforward methodology toward C1 bridged ansa ligands. After double deprotonation with n-BuLi and reaction with ZrCl4, C1-symmetric ansa zirconocene dichloride complexes were obtained that display excellent properties in propylene polymerization.266 Several research groups have contributed to this area over the last 25 years.267−278 Depending on the steric bulk on the fluorene and fulvene moiety, different selectivities in the polymerization of propylene could be obtained. Several racemic chiral-at-ansabridged group 4 metal complexes were recently prepared by Carpentier and co-workers and used in highly iso selective propylene polymerization (Scheme 93).268 Erker et al. studied the addition of alkyllithium reagents to dialkylaminofulvenes, which provided, after transmetalation, group 4 metallocene dichloride or dimethyl complexes. In the latter case, addition of borane led to a cationic metallocene complex stabilized through the coordination of nitrogen to the metal, which underwent C−H activation and alkene insertion reactions.226 Addition of methyl- or phenyllithium to 6-alkylsubstituted fulvenes and transmetalation with ZrCpCl3 yielded

Scheme 89. Synthesis of Mono-Cp Osmium and Ruthenium Complexes from Hydride Precursors

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Scheme 90. Exocyclic Hydrostannylation of Tetramethylfulvene Dependent on a Tin-Hydride Precursor

Zirconium and hafnium tetrabenzyl complexes 349 reacted smoothly with 6,6-dimethylfulvene to selectively afford the monocyclopentadienyl zirconium and hafnium tris(benzyl) complexes (Scheme 99), whereas in the case of 6,6diphenylfulvene only Hf yielded a clean reaction.290 Interestingly, no proton abstraction from the methyl group at C6 position was observed. 6.1.3. Addition of Nitrogen or Phosphorus Nucleophiles onto Pentafulvenes. In a leading review, Erker described the synthesis of aminoalkyl-Cp and phosphinoalkylCp group 4 metal complexes derived from fulvenes, with a special focus on constrained geometry complexes.226 Ammonia or lithium amides can substitute the amino group in 6dimethylaminofulvene, giving rise to new 6-aminofulvenes for further functionalization. Lithium amides add to the exocyclic double bond in 6-tert-butylfulvene, providing suitable LiCp precursors for transmetalation. Lithium phosphides add to the exocyclic fulvene bond to provide phosphine substituted lithium Cp precursors for transmetalation onto Fe,291,292 Cr,293 Ti,294−296 Zr,294−296 and Nb297 (Scheme 100). In one case, the intermediate phosphine adduct 352 initially yielded the transmetalation product 353, which then underwent reductive cleavage to furnish biscyclopentadienyl ansa complex 354.295 It should be noted that, in contrast to lithium amides, the less basic lithium phosphides can add to fulvenes bearing enolizable alkyl groups at the 6-position. 6.1.4. Reductive Dimerization of Pentafulvenes. The reductive dimerization of fulvenes with main group or transition metals is a long-standing research topic that dates back to the 1960s. Shapiro has reviewed this chemistry up to 2002, and Tacke has summarized his contributions in this area until 2008.225,228 This straightforward approach readily gives access to ansa-metallocene derivatives of Ca for transmetalation to numerous transition metals,228 of Zr for polymerization catalysis,228,298 and of Ti for anticancer activity.225 However, since the observation that ansa-titanocenes show less effective anticancer activity as compared to their nonbridged metallocene counterparts, interest in the reductive dimerization has decreased since 2006. Only very recently were new ansa-calcocene 357 and titanocene 358 complexes reported by reductive dimerization of 1,2,3,4-tetramethylfulvene. Surprisingly, this was the first example of reductive dimerization with unsubstituted fulvenes at the exocyclic position (Scheme 101).299 Complex 358 could be reduced with magnesium to furnish the alkyne-stabilized complex 359, which was reacted with stoichiometric amounts of water to investigate the elemental steps of water-splitting. 6.1.5. Deprotonation α to the C6 Position. 6.1.5.1. Deprotonation of C−H. Fulvenes substituted with alkyl groups at the C6 position can be readily converted to the corresponding

Scheme 91. Synthesis of an Enantiopure Ruthenocene Complex Starting from a Chiral Fulvene

Scheme 92. Reductive Complexation of RhCl3 to a Silylated Fulvene

Scheme 93. Synthesis of Group 4 Metallocenes with Chiral-atansa-Bridged Ligands

the exocyclic double bond seems to be essential (Scheme 98).289 The obtained Cp products 347 and 348 were then transformed to the corresponding titanocene-dichloride complexes, which showed very good anticancer activity. 3958


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Scheme 94. Synthesis of an Enantiopure Zn Complex from a Chiral Hybrid Cp/Scorpionate Ligand

with Ca, whereas Mg does not yield the deprotonation product.235,300−302 Zr(NMe2)4 reacted with 6,6-dimethylfulvene to selectively yield (Cpi)Zr(NMe2)3 or (Cpi)2Zr(NMe2)2 (Cpi = C5H4C(CH3)CH2), depending on the stoichiometry.290 In an attempt to synthesize rhodium mono- and bis(diolefin) complexes for the oligomerization of butadiene, the Rh(I) triflate precursor 360 was reacted with dimethylfulvene. However, instead of an expected Rh(fulvene) complex, the alkenylsubstituted rhodocene 361 was isolated. Intramolecular C−H activation in a postulated Rh(bisfulvene) complex was suggested instead of fulvene reduction via a Rh−H intermediate (Scheme 102).303 A ruthenocene-appended chlorin complex was obtained from the reaction of 13′-fulvenylchlorin and RuCp*(cod)Cl in the presence of TEA.304 Upon complexation, an additional double bond is generated in ring E, which weakens the ring current of the chlorin moiety and makes the molecule prone to rapid autoxidation. Camphor-derived fulvene reacted with different lithium reagents to yield mainly the deprotonation product, which afforded the corresponding chiral ferrocene after transmetalation with FeBr2.305 Jaouen reported a straightforward synthesis of CpRe(CO)3-substituted steroids 363 by deprotonation γ to the C6 position (Scheme 103). Deprotonation at the α position occurred only in trace amounts.306 6.1.5.2. Deprotonation of OH and NH. In a fashion similar to the deprotonation of C−H groups α to C6, heteroatom bound protons (OH or NHR) α to C6 can also be readily removed, leading to the corresponding Cp ligand. Diversely substituted 1acyl- or 1-iminoacyl-6-hydroxy or -6-aminofulvenes ([O,O], [N,O], [N,N] fulvenes) are readily deprotonated, leading to the corresponding cyclopentadienyl ligands, which coordinate to the metal through either the heteroatoms, the Cp ring, or in certain cases not at all. The groups of Bildstein and Bailey have investigated the synthesis of neutral or cationic ruthenocenes and rhodocenes starting from various [O,O], [N,O], [N,N] fulvenes (Schemes 104 and 105), which can serve as redox-responsive metalloligands.307−311 Pampaloni and co-workers investigated several [O,O] fulvenes in reactions with M(η6-arene)2 precursors.312 In the case of pmcpH 374, it was found that with the harder early transition metals Ti, V, and Nb, the formed pmcp anion displaces the arene ligands and binds in a κ2-O,O′-fashion, whereas with Cr and Mo, cationic metal complexes 379 are formed with nonbound pmcp ligands as counteranions (Scheme 106). The chromium complex was the first [Cr(toluene)2]+ cation containing a cis-eclipsed arrangement of toluene rings to be studied by X-ray, EPR, and electrochemistry.313−315

Scheme 95. Synthesis of Chiral Ferrocenes from Achiral Fulvenes

Scheme 96. Synthesis and Metal Complexation of Hybrid Cp*/NHC ligands

Scheme 97. CuI-Catalyzed Addition of Grignard Reagents onto Fulvene

alkenylcyclopentadienes under basic conditions. Even though this reaction can be an undesired side-reaction in reductive dimerization or carbometalation reactions, this approach has been elegantly employed by Erker and co-workers to access alkenyl-substituted metallocene complexes of lithium, calcium, titanium, and zirconium. This chemistry was recently reviewed by Erker.227 These complexes have triggered the development of functional group chemistry on air-sensitive metal complexes, which had long been restricted to ferrocenes. Upon photochemical transformation or metathesis reactions, these complexes yielded ansa-complexes having various chain lengths. Starting from 6-alkyl,6-dimethylaminofulvenes, intramolecular Mannich reactions have become accessible. In polyunsaturated chains on the exocyclic position, deprotonation occurs on the ωCH3 group. Bis(trimethylsilylamide) complexes of Ca, Sr, Ba, as well as dimethylmagnesium deprotonate 6-methyl-6-phenylfulvene to yield the corresponding sandwich complexes [M(C5H4C(Ph) CH2)2(thf)2]. With dicyclopropylfulvene, the reaction is slow 3959


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Scheme 98. CuI Phosphoramidite Promoted ZnEt2 Addition to 6-Arylpentafulvenes

precursor yielded the mixed ligand ruthenocene complex 386 (Scheme 108).40

Scheme 99. Synthesis of Monocyclopentadienyl Zirconium and Hafnium Tris(benzyl) Complexes

6.2. Pentafulvenes as Ligands in Organometallic Complexes

Because of their unique cross-conjugated electronic system, fulvenes display a wide array of coordination modes to metals. Often these binding patterns are subject to discussion and represent extreme situations, with the reality being mainly found in between the different possibilities (Figure 5). The following sections will describe the prevalent synthetic methods to prepare metal−fulvene complexes and their reactivity patterns. 6.2.1. Synthesis by Neutral Ligand Displacement. For late transition metals, this synthetic pathway has been that explored most frequently. Metal−carbonyl complexes readily undergo exchange with fulvenes to furnish either monomeric fulvene−metalcarbonyl complexes or bimetallic fulvene complexes. The early chemistry of iron and ruthenium carbonyl complexes is nicely summarized by Weiss in papers from 1975.319,320 Depending on the reaction conditions and the fulvene substitution, various coordination modes were observed. Later, Ogino investigated the coordination of Fe and Ru to tetramethylfulvene, giving access to bimetallic fulvene complexes

Recently, it has been shown that Cr can also bind in a κ2-O,O′fashion to [O,O] fulvene derived anion 381 (Scheme 107).316 Complex 382 showed good activity in ethylene polymerization at room temperature. Related to this field is the work by Erker on the variable complexation of Zr, Fe, and Ru to the 1,2-bis(N-tbutylcarbamoyl)cyclopentadienide reagent.317,318 6.1.6. Miscellaneous. The ylidic character of certain pentafulvenes can be enhanced by electron-donating groups, for example, 6,6-dimethylaminofulvene (see section 2.1), leading to direct reaction with metal halide precursors. Kunz and coworkers have shown that imidazoline-based fulvenes 383 react with FeCl2 in the presence of NaBF4 to the corresponding ferrocenes 384 and 385. In analogy, the Cp*Ru(II)OTf

Scheme 100. Addition of a Lithium Phosphide to Fulvene and Conversion to Metallocenes

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Scheme 101. Reductive Dimerization of Tetramethylfulvene with Ca or TiCl2

Scheme 102. Synthesis of Alkenyl-Substituted Rhodocene

Scheme 104. Synthesis of a Rhodocene from a [N,N] Fulvene

387 with a η5:η1 coordination pattern (Scheme 109).81,321 Addition of phosphines was selective at the less substituted metal center. With secondary phosphines, a bimetallic phosphidobridged complex 389 was obtained after hydrogen transfer onto the fulvene ligand (Scheme 109). Addition of dppm led to monomeric species, whereas with dppe a dimeric complex was obtained. In the case of Ru, the addition of PMe3 leads to two isomers, 390 and 391, probably due to the metal’s larger size as compared to that of Fe. More recently, new Fe and Ru fulvene complexes were obtained under harsher conditions, and these were characterized by X-ray studies. No explanation has yet been given for the formation of these complexes (Scheme 110).322,323 For chromium and molybdenum fulvene complexes, the precursor of choice is M(MeCN)3(CO)3,324−326 as shown, for example, in the synthesis of the fulvenyl-azulene Cr complex 399 in Scheme 111. Recently, the 6,6-dimethylfulvene chromium complex could be structurally characterized by X-ray studies and DFT calculations.326 From these studies, the authors disclosed their preference for the η2:η2:η2 description over the η5:η1 binding mode. The reaction of Mo(CO)6 and Re2(CO)10 with fulvenes led to the corresponding Cp complexes or abstraction of protons α to C6 (Scheme 112).327,328 An important contribution was made in 1985, concerning the displacement of arene ligands from M(η6-arene)2 complexes (M = Ti, Mo, W) with bulky fulvenes (Scheme 113).329 6.2.2. Reduction of Metal Precursors in the Presence of Pentafulvenes. A ground-breaking discovery concerning the

coordination of fulvenes to group 4 metals was made by the group of Beckhaus in 2001.330 The reduction of Cp′TiCl3 precursors 361 (Cp′ = C5H5 or C5Me5) with Mg in the presence of 6-tert-butylfulvene led to the isolation of complexes of the type Cp′(η5:η1-fulvene)TiCl 410 in a highly diastereoselective manner (Scheme 114). X-ray studies showed the classical bending of the exocyclic double bond toward Ti (angle 35.6°) and an elongated Ti−C6 bond (2.355 Å), as compared to nonsubstituted fulvene complexes (2.281 Å). UV−vis data of the green complexes indicated weak d−d transitions, in agreement with some electron density remaining on Ti. Interestingly, the titanium complex derived from 6,6-bis(ptolyl)fulvene shows fluxional behavior around the Ti−Ct axis (Ct = centroid of the fulvene ring carbon atoms) in NMR studies at room temperature despite the observation of a Ti−Cexo bond (2.535 Å) in the X-ray structure.331 The nucleophilicity of the exocyclic carbon upon coordination to Ti was demonstrated by the reaction with simple electrophiles (HX, X = OH, Cl, RO), resulting in the formation of mixed titanocene complexes.330 Different ketones, for example, acetone, benzophenone derivatives, or camphor, could also be inserted into the Ti−Cexo bond of 410, some of which with good diastereoselectivity, depending on steric and electronic parameters.332 In most cases, an equilibrium between the cis and the trans isomer was observed (Scheme 115). Insertion reactions with nitriles led to new product 415, in which the stereochemical information is lost because of an imine−enamine rearrangement. However, switching to a fulvene without hydrogen on the exocyclic position allowed the isolation

Scheme 103. Synthesis of CpRe(CO)3-Substituted Steroids

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Scheme 105. Synthesis of Ruthenocenes from [N,O] Fulvenes

Scheme 106. Investigation of [O,O] Fulvenes with Various M(η6-Arene)2 Complexes

Scheme 108. Synthesis of Imidazolium-Substituted Metallocenes

Scheme 107. Reaction of [O,O] Fulvene with CrCl3

electron density, via N(pπ) to Ti(dπ) interactions, to reach an 18e configuration. When the reduction of Cp*TiCl3 with Na in the presence of different bulky fulvenes was conducted under an atmosphere of dinitrogen, the dimeric titanium−nitrogen complexes 419 could be isolated (Scheme 117).334 The dinitrogen moiety is bound in an end-on fashion in an almost linear arrangement. The N−N distance is only slightly longer than that in free N2, indicative of a small degree of N2 activation. Interestingly, the two fulvene moieties are on the same side of the complex, displaying the usual structural features of Ti−fulvene complexes. The dinitrogen

of an analogue of the initially formed imine complex 414 (Scheme 116).333 Isonitriles did not lead to 1,2 insertion, but 2 equiv of isonitrile inserted in the Ti−Cexo bond, leading to intermediate 417, which slowly rearranged to final product 418 (Scheme 116). The authors conclude that the rearrangements are a consequence of the titanium center striving for higher 3962


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provided the titanocene dichloride complex. The fulvene and benzofulvene complexes were then investigated as catalysts for intramolecular hydroamination reactions of geminally disubstituted alkenes.338 It could be shown that the benzofulvenebased complex gave the best results. Reactions with primary anilines led to the formation of the expected titanocene bisamido complexes 427. In contrast to primary amines, only monoprotonation of the complex, as in 428, was observed, and no titanocene−imido complex could be isolated. However, the use of 1 equiv of diphenylhydrazine led to the titanium hydrazide complex 429, whereas the reaction with 2 equiv gave the monocyclopentadienide(bishydrazide)titanium complex with liberation of one cyclopentadiene molecule (Scheme 119). Very recently, the bis(fulvene)Ti complex 425 was shown to readily react at room temperature with methylaniline derivatives 430 to yield titanoceneaziridene complexes 431 by C−H activation of the methyl group (Scheme 120).339 These complexes show good stability and underwent hydroaminoalkylation of 1-octene. They could be further reacted with alkynes, carbonyl compounds, and nitriles. The synthetic approach employed for the bis(fulvene) titanium complexes could be extended to the corresponding Zr complexes.340 Reduction of ZrCl4 with Na/Hg in the presence of diarylfulvene yielded bis(η5:η1-fulvene)Zr(thf) complexes, which show chirality at the zirconium center. Weaker M−Cexo π back bonding was concluded from the X-ray structure: the Zr−Cexo is longer and less bent than comparable Ti or Zr fulvene complexes. As with other fulvene complexes, these complexes react with H acidic substrates (HCl, H2O, and primary and secondary amines) and undergo insertion reactions with nitriles, imines, and ketones. Most interestingly, complex 432 activates molecular hydrogen at room temperature to yield bridged hydride complex 433 (Scheme 121). Despite the presence of excess hydrogen, only one Zr−fulvene bond is reactive, while the other Zr−fulvene moiety stays intact. 6.2.3. Generation of Pentafulvenes in the Coordination Sphere of Metals. 6.2.3.1. C−H Activation Pathways. In the previous two sections, the conversion of fulvenes into fulvene− metal complexes was described. This part deals with the formation of fulvene−metal complexes via C−H activation of an alkyl-substituted Cp ligand, in most cases Cp*, in the coordination sphere of a metal. For early transition metals and felements, the so-called “tuck-in” complexes can be obtained by

Figure 5. Various binding modes of transition metals to pentafulvenes.

could be removed under vacuum to yield the paramagnetic trivalent Ti complex 420 (Scheme 117). Complex 419 was investigated to access cationic complexes (Scheme 117).335 Upon addition of the Brønsted acidic borate reagent [PhNMe2][HBPh4], the reaction outcome was solvent dependent. In toluene, Ti−phenyl interactions were observed in the cationic metallocene 421, whereas in THF the cationic complex 422 containing two THF molecules was isolated. With B(C6F5)3, the reaction did not furnish the expected zwitterionic complex derived from attack on the exocyclic carbon, but instead a product of attack at the endocyclic ring followed by rearrangement. The titanium center in 423 is stabilized by a Ti−F bond (Scheme 117). Theoretical studies on the new titanium−fulvene complexes were in good agreement with the experimental results. The η5:η1 dianion-like description seems most appropriate for these complexes.336 The reductive complexation approach of fulvenes to low-valent titanium centers was further developed toward bis(η5:η1-fulvene)titanium complexes 425 (Scheme 118).337 Whereas low-valent group 4 metal halides (MCl2·2THF, M = Ti, Zr, Hf) provided reductive dimerization of fulvenes and hence the ansa-metallocene complexes,298 the reduction of TiCl3 with Mg in the presence of the bulky fulvenes yielded the unsolvated bis(fulvene) titanium complexes. This approach was also valid for bulky benzofulvenes. The complexes are chiral and show shorter Ti−Cexo bonds as compared to the Cp*FvTiCl analogues. Addition of HCl

Scheme 109. Synthesis and Reactivity of Bimetallic Fulvene-Bridged Iron and Ruthenium Complexes

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Scheme 110. Synthesis of Bimetallic Fe and Ru Fulvene Complexes from 6,6-Disubstituted Fulvenes

Scheme 111. Synthesis of a (1-Fulvenyl-4,6,8trimethylazulene)Cr(CO)3 Complex

Scheme 113. Synthesis of Metal Fulvene Complexes from M(η6-Arene)2 Precursors

ligand-induced proton abstraction or insertion of the metal into the C−H bond under thermal or photochemical conditions. A canonical form of the dianionic tuck-in complex is the neutral fulvene complex. Such tuck-in complexes are known for Sc,341 La,342 U,343,344 Th,345 Ti,346−353 Zr,354−358 Hf,359,360 Nb,361−363 and Ta.364,365 The metal−Cexo bond is nucleophilic in these complexes, favoring reaction with numerous electrophiles (HX, H2S, aldehydes, ketones, nitriles, isonitriles, boranes, alkynes). The reactivity of the complexes described in the previous section

6.2.2 parallels the reactivity of these tuck-in complexes and will not be detailed further here. As an example of the reaction with

Scheme 112. Reaction of Mo and Re Carbonyls with Fulvenes

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Scheme 114. Synthesis of Cp′(η5:η1-Fulvene)TiCl Complexes under Reductive Conditions

observed with early transition metals. It has been proposed that this reaction occurs via a metal−hydride intermediate. This chemistry has been reviewed by Kreindlin in 2004 and by Gleiter in 2007, and herein we will highlight a few recent examples.229,230 A theoretical study on the structural parameters of α-metallocenylmethylium ions and related neutral fulvene complexes was published in 2009, showing good agreement with experimental findings when steric hindrance at the exocyclic carbon is small.366 Heinekey reported the synthesis of an iridium fulvene complex 437 by oxidative C−H abstraction of the Cp* ligand with a trityl salt in a Cp*Ir(NHC) complex 436 (Scheme 123).367 The reaction was proposed to proceed via an electron-transfer from iridium to trityl followed by H atom transfer. During the homogeneous catalytic reduction of dioxygen, deactivation of the transfer hydrogenation catalyst 438 occurred presumably via the fulvene intermediate 439 (Scheme 124).368 The complex reacts further with aminoborane to the iridium hydride complex 440. Rhenium−fulvene complexes have been studied for a long time. Recently, the reaction of complex 441 with KPPh2 or vinylmagnesium bromide followed by acidic treatment yielded the CpReH complexes 443 and 445 (Scheme 125).369,370 Kreindlin et al. obtained various Cp*Ru−fulvene complexes under strongly acidic and oxidizing conditions (Scheme 126).371 The coordination of β-diketoiminate ligands to [Cp*RuCl2]2 led in the case of bis-CF3-substituted ligand 451 to the Ru(βdiketoiminate)Fv complex 454 (Scheme 127).372 6.2.3.2. [2+2+1] Cyclotrimerization Reactions. As described in the section on fulvene synthesis (section 3.2), transitionmetal-catalyzed [2+2+1] cyclotrimerization of terminal alkynes readily gives access to substituted fulvenes. In certain cases, stoichiometric reactions allowed the isolation of late-transitionmetal fulvene complexes. Early examples include the cationic Rh(I)-catalyzed trimerization of tert-butylacetylene, leading to a Rh(I)(η4-fulvene) complex,373 and the group 6 metal-catalyzed trimerization of a silyl-bridged tris(acetylene) framework.374 The reaction of iridacyclopentadiene complex 455 with various terminal alkynes in the presence of AgBF4 gave the cationic Ir(η2, O-κ1-fulvene) complexes 456, which reacted further to give various Ir−fulvene complexes depending on their substitution (Scheme 128).375 Complex 456 could only be

Scheme 115. Stereoselective Insertion of Carbonyl Compounds into the Ti−Cexo Bond

alkynes, the reaction of the Cp*FvTi complex 434 with a large variety of internal alkynes is shown in Scheme 122.347 For late transition metals, various bonding situations can be considered. In addition to the tuck-in and neutral fulvene binding mode, an additional zwitterionic structure also needs to be considered. In addition, pure η2 or η4 binding has also been observed (Figure 5). The reactivity of these complexes with nucleophiles is maintained as in the free fulvenes, for example, addition of phosphines or Grignards on the exocyclic fulvene carbon. The reaction with protic acids (HX) is unusual, which leads to the formation of the Cp* ligand and a M−X bond, as

Scheme 116. Insertion and Rearrangement with Nitriles and Isonitriles

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Scheme 117. Synthesis and Reactivity of Titanium−Dinitrogen Complexes

isolated for R1 = t-Bu. In other cases, for example, for R1 = Ph, complex 456 reacted further to yield complex 457, which was shown via X-ray crystallography to possess a significant contribution of the charge-separated species. The reaction of osmium-allenyl carbene complex 458 with trimethylsilylacetylene or diphenylbis(acetylene) furnished the osmium−fulvene complexes 461 and 462 with rather different coordination characteristics (Scheme 129), as established by Xray studies.376 Whereas complex 461 exhibits bending angles and a C5−C6 bond length comparable to those of other Os−fulvene complexes close to the η5:η1 “tuck-in” arrangement, complex 462 is much closer to the neutral 2+2+2 6π coordination. A possible explanation for this could be the bulky SiMe3 group at the 1 position, which hinders the metal−C6 coordination. Mo−tetracyclone complex 463 has been shown to induce oligomerization of phenylacetylene and p-tolylacetylene to yield the 2,3,6-triphenylfulvene complexes 464 (Scheme 130).377 The most remarkable feature of this reaction is the observed regioselectivity as, in most TM-catalyzed processes, the 1,3,6 fulvene isomer is formed. The presence of the bulky tetracyclone moiety seems to force the unfavorable tail-to-tail coupling of two phenylacetylenes. The bonding situation in 464 was described as a η5:η1 “tuck-in” 6π coordination (bond angle 33−35°, Cexo (1.43 Å) is longer than that in free fulvene (1.34 Å)). The Ru(Tp)Cl(cod) complex 465 reacted with phenylacetylene in refluxing alcohol to form the RuCp(Tp) complex 466 (Scheme 131).378 However, in the presence of 1 equiv of NH4PF6, the cationic Ru(fulvene) complex 467 was obtained. It should be noted that 466 can be transformed to 467 upon addition of NH4PF6, whereas 467 cannot be converted to 466 even in refluxing methanol. The Pd(II)-mediated cyclotrimerizaton of phenylacetylene in the presence of trimethylamine yielded the Pd(η2-1,2,4triphenylfulvene) complex 469, which was structurally characterized (Scheme 132).379 The lability of the fulvene to metal binding was apparent upon addition of DMAD, which led to the

Scheme 118. Synthesis of Bis(η5:η1-fulvene)titanium Complexes

Scheme 119. Reaction of a Bis(fulvene)Ti Complex with Anilines, Primary Amines, and Hydrazine

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Scheme 120. C−H Activation with a Bis(fulvene)Ti Complex toward Aziridine Complexes

Scheme 121. Hydrogenation of a Bis(η5:η1-fulvene)Zr Complex

Scheme 125. Reaction of Rhenium−Fulvene Complexes with Nucleophiles

Scheme 122. Insertion of Alkynes into a Cp*FvTi Complex

Scheme 123. Oxidative C−H Abstraction in a Cp*Ir(NHC) Complex

Scheme 126. Synthesis of Cp*RuFv Complexes under Strongly Acidic Conditions

Scheme 124. Catalyst Deactivation by Fulvene Formation

terminal alkynes in ethanol and in the presence of various nucleophiles.381 6.2.4. Miscellaneous Organometallic Complexes with Pentafulvenes. In certain cases, the metal is not bound to the fulvene moiety but to the exocyclic group of the C6 position. The iso-Cr(CO)3 fulvene complex 472 shows binding of the metal to the phenyl group at the C6 position of the fulvene.324 It was obtained by condensation of the precoordinated benzophenone with NaCp (Scheme 133). A similar approach was employed for the CpMo(CO)3Me−fulvene complex 474.382 The aminofulvene bound tungsten complex 476 was obtained by thermolysis of tungsten vinyl complex 475 in the presence of CpH (Scheme 134).383 The reaction was proposed to proceed via a β-H reductive elimination of SiMe4, leading to Cp*W(NO)(η2-PhCCH), which undergoes nitrile insertion. The fluxional behavior of aminofulvene ligand in 476 was studied by NMR spectroscopy. Complexes with palladium or platinum bound to the C6 position of fulvene were obtained by formal insertion of nitriles

liberation of fulvene and formation of the Pd-alkyne complex 470. The origin of the unusual regioselectivity of the trimerization process is yet to be determined. The η2 bound fulvene exhibits typical Pd−alkene interactions (Pd−C and C C bond lengths). Metal−fulvene intermediates have also been postulated as highly plausible intermediates in the following reactions: (i) reaction of an osmium pincer complex with phenylacetylene leading to μ-bisCp-bridged bimetallic complexes,380 and (ii) the Rh(III)-mediated synthesis of several cationic bis(cyclopentadienyl)Ru(III) complexes by cyclotrimerization of 3967


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Scheme 127. Synthesis of a Ru(β-Diketoiminate)fulvene Complex

Scheme 128. Fulvene Complexes from Iridacyclopentadiene Complex

Scheme 130. Synthesis of a Mo−Fulvene Complex through 2+2+1 Cyclization

Scheme 131. Synthesis of Cationic Ru(fulvene) Complex

into a Pd−Cp or Pt−Cp bond. Depending on the metal, different regioisomers were observed (Scheme 135).384,385 Dong et al. studied the coordination of silver salts to a wide series of pyridazine-containing fulvene ligands, leading to coordination polymers. In 482, the silver coordinates to the exocyclic nitrogen and the thiophene group, among others (Figure 6). The oxidation of related fulvene−ferrocene complexes was studied, providing access to cyclopentenediones.386,387 Finally, an unusual phosphine bound chromium fulvene complex 484 was synthesized by Edelmann using the Cr(CO)5 precursor (Scheme 136).324

Depending on the type of carbene complex used, it is possible to create versatile carbon synthons for organic synthesis. While observing the reactivity of the alkenyl carbene complex 485 with dimethylfulvene, Barluenga et al. obtained substituted indene 486 via a [6+3] cycloaddition. This report is considered as the first report on the [6+3] cycloaddition of metal carbene complexes, and offered an unusual approach to indene synthesis. The current protocol provides a easy benzannulation of the fulvene system, instead of the annulation of the cyclopentene unit into the benzo ring. The reaction was found to be successful with a range of alkyl and alkenyl fulvenes and afforded some substituted indanones and indenes in a regioselective manner (Scheme 137).389 A systematic carry-over of the strategy resulted in the most primitive cyclopropanation and cycloheptannulation of the

6.3. Transformation of Pentafulvenes via Metal-Catalyzed Reactions

6.3.1. Unusual Cycloaddition Partners of Pentafulvenes: Fischer−Carbene Complexes. The early part of the current era witnessed the introduction of a novel reactivity pattern of pentafulvenes, and its rapid recognition as a general protocol for the synthesis of substituted indenes and annulated cyclopentanones. This methodology has been attributed to the efforts of Barluenga, who amalgamated the captivating chemistry of pentafulvenes with Fischer carbene complexes. Heteroatom stabilized carbene complexes have proven to be useful organometallic reagents for carbo- and heterocyclization reactions.388

Scheme 129. Synthesis of Osmium Fulvene Complexes through 2+2+1 Cyclization

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Scheme 132. Synthesis of a Pd(η2-1,2,4-Triphenylfulvene) Complex

Scheme 133. Synthesis of Cr and Mo Complexes Bound to the Fulvene C6 Substituent

Figure 6. Coordination of silver to a pyridazine-containing fulvene.

Scheme 136. Synthesis of an Unusual Phosphine-Bound Cr− Fulvene Complex

Scheme 137. [6+3] Cycloaddition of Alkenyl Carbene Complexes with Dimethylfulvene

Scheme 134. Synthesis of a Tungsten−Aminofulvene Complex

Scheme 138. [2+1] Cyclization of Pentafulvene with Alkyl or Aryl(methoxy) Carbene Complexes pentafulvene system with Fischer carbene complexes. The cyclopropanation of pentafulvenes was accomplished via a [2+1] cyclization with alkyl or aryl(methoxy) carbene complex 488. The successful extension of concept resulted in the more elaborate cyclopentane framework 490 (Scheme 138).390 With pentafulvenes, alkynylcarbene complexes 491 led to similar cyclizations under conventional conditions; however, the presence of CO altered the reaction pathway, inducing [4+3] cyclization and leading to cycloheptane skeleton 493 (Scheme 139).390

An efficient entry to amino indenes 495 was then established via a regioselective [6+3] cycloaddition reaction of alkenylaminocarbene complex 494 with pentafulvenes (Scheme 140).391 The pentafulvene−Fischer carbene combination offers an exceptional protocol for entry into substituted indenes and

Scheme 135. Synthesis of 6-Pd and 6-Pt Coordinated Fulvene Complexes

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isomerized selectively to 1-substituted 1,2-dihydrofulvenes 498.394 The CC double bond migration could also be catalyzed by titanium hydride, allowing a one-pot procedure to provide 1-substituted 1,2-dihydrofulvenes from pentafulvenes via two titanium-catalyzed steps. This sequence was proven to be temperature dependent, allowing selective access to conjugated or nonconjugated adducts by simple temperature tuning.

Scheme 139. Reaction of Alkynylcarbene Complexes with a Pentafulvene

7. THEORETICAL PERSPECTIVES AND PHOTOPHYSICAL PROPERTIES OF PENTAFULVENES Pentafulvenes are model compounds for testing the theoretical predictions of aromaticity, reactivity, photophysical, and photochemical processes, and this provides interesting information about the relationships between their electronic structure, physical, and chemical properties.398

Scheme 140. [6+3] Cycloaddition of Alkenylaminocarbene Complexes with a Pentafulvene

7.1. Aromaticity and Substitution Effects

various annulated cyclopentanoids. Remarkably, the indenes gained through this strategy preserve a reactive fulvene unit and are potential candidates for the synthesis of attractive polycyclic systems. 6.3.2. Hydrometalation Reactions of Pentafulvenes. Until recently, the reactivity of organometallic reagents with fulvenes was mainly focused on nucleophilic addition reactions, leading to exocyclic attack at the C6 position. In contrast, our group has focused on the possibility of selectively activating endocyclic double bonds. The first success was achieved in the form of hydrotitanation, in which [Ti−H], generated in situ by a reaction of Cp2TiCl2 with Dibal-H, was selectively added to the endocyclic double bond of fulvene. This led to the formation of an allyl titanium/aluminum reagent, which was trapped by aldehydes to form the corresponding homoallylic alcohols 496 with excellent diastereoselectivity but in moderate yields.392 The synthetic potential of the methodology was illustrated by the diastereoselective synthesis of highly substituted cyclopentanones 497. In further studies, it was found that a catalytic amount of titanium is sufficient to direct the reaction toward the desired outcome (Scheme 141). These new conditions made the transformation of monosubstituted fulvenes and the trapping with ketones possible.393 Subsequently, a unique isomerization of the allylic alcohols derived from fulvenes could be achieved under zirconium/titanium-catalyzed conditions. Under zirconium-catalyzed condition, 1-substituted 1,4-dihydrofulvenes

Aromaticity is an important concept in organic and inorganic chemistry for justifying the stability, reactivity, molecular structure, and properties of many organic and inorganic compounds.19 Fulvenes are nonalternant hydrocarbons, which is often taken as a model for studying the aromaticity of that class of compounds, where the π-density is shifted from the exocyclic olefin to the endocyclic aromatic five-membered ring. The unique conjugated structures and questions regarding the aromatic/antiaromatic character make them attractive candidates for the theoretical chemist.20 Exocyclic substituted fulvenes represent an excellent class of model compounds for studying substitution effects, due to the differences in delocalization. It is difficult to reproduce the dipole moment of pentafulvene using ab initio molecular orbital models,395,396 even though modern semiempirical calculations can reproduce this.397 However, it is possible to demonstrate the effect of electron correlation on the calculated dipole moments of fulvene and cyclopentadiene using ab initio molecular orbital theory. Fulvenes are alkylidene derivatives of 1,3-cyclopentadiene. Although the experimentally determined dipole moment of 1,3-cyclopentadiene can be reproduced with HF using a large basis set, the dipole moment of fulvene is more intricate computationally. It was found that MP2 gives a worse result than HF, and higher-order electron correlated methods such as MP4 and QCI show that the quality of the computed dipole moment

Scheme 141. endo-Selective Hydrometallation of Pentafulvenes

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depends on how well the electron correlated method corrects the π-component of the dipole moment.398 The structures of fulvenes, fulvalenes, and related molecules were calculated by using ab initio calculations employing conventional (HF/6-31G(d) and MP2/6-31G(d)) and density functional theory (B-LYP/6-31G(d)) methods.399 When comparing 1,3-cyclopentadiene with fulvene using all of these levels of theory, the only difference noted is the significantly shorter C−C single bonds to C1 and the larger internal bond angle at C5, due to the change in hybridization at the carbon center (Figure 7). Their calculated dipole moments were in good agreement with the experimental results produced by Baron et al.22

Figure 9. Aromaticity order for five-membered rings. Reproduced (adapted) with permission from ref 401. Copyright 2003 Royal Society of Chemistry.

(HOMA) model and nucleus independent chemical shift (NICS) index, after plotting it against the σ+p (for electrondonating substituents, in the case of pentafulvene) and the σ−p (for electron-accepting substituents, in the case of heptafulvene) scales of substituent constants.403 This method provides an approximate evaluation of the resonance power, independently of side-reactions such as tautomerization or side-processes (e.g., different stabilization by solvent effects on two sides of the equilibrium reaction), which in some cases may bias the experimental data. Later, a comprehensive analysis of the effect of substituents on the aromaticity of fulvene was developed. The fulvene, with a positive aromatic stabilization energy (ASE), having the HOMA value of one, and a negative NICS, will be aromatic, and will be nonaromatic if the reverse is true.404 When the substitution changes, the geometry, the energy, and the response toward the applied external magnetic field will change accordingly. This behavior demonstrates the influence of changing a substituent on the degree of aromaticity, stability, and other physicochemical properties. Sache and co-workers reported the first observation of a triplet state in a compound with a pentafulvene π-electron system. Lowenergy electron-energy-loss spectra of 6,6′-dimethylfulvene placed on a thin film of solid argon were measured at 16 K.405 Extensive efforts were later made to determine whether or not fulvenes are “aromatic chameleons”.406 The prior behavior was rationalized by application of Hückel’s rule for the S0 state and Baird’s rule for the T1 state (Figure 10a).407,408 As a result, fulvenes are dipolar in the T1 state but opposite in direction to

Figure 7. Molecular structure and atom numbering of cyclopentadiene and pentafulvene.

To understand the influence of the structural variables on the geometries, stabilities, and the reactivities of ketenes, ab initio calculations of structure and energies are more informative. In this context, Tidwell and co-workers demonstrated the antiaromatic destabilization of ketenes (triafulvenone and heptafulvenone), and the aromatic stabilization of pentafulvenone (Figure 8) as compared to pentafulvene. This is most

Figure 8. Molecular structures of fulvenones.

prominent in isodesmic energy comparisons of 6-31G(d)//631G(d) calculations and was justified by electronic properties such as dipole moment, atomic charge, and bond length comparisons.400 This behavior is attributed to the enhanced stabilization of pentafulvenone and the enhanced antiaromatic destabilization of other fulvenones. The aromaticity and antiaromaticity of three-, five-, seven-, and nine-membered conjugated ring systems with exocyclic substituents are well characterized by energetic, magnetic, and geometric criteria. These were computed at the B3LYP/6311G**//B3LYP/6-311G** for those rings with an exocyclic methylene, keto, ketenyl, and diazo substituents by Tidwell and co-workers.401 From their studies, it was well documented that the aromaticity order for three- and seven-membered rings is according to cation > ketone > fulvene > diazoalkane ≈ ketene, which is reversed for five- and nine-membered rings (Figure 9) and also shows a decrease in the degree of aromatic/antiaromatic character with the ring size. In 1998, Liebman and co-workers derived a unique mathematical equation by considering a thermochemical-based model for the aromaticity of some common molecules, including fulvene.402 In 2001, a new method of determining resonance effects was established by using substitution effects on aromaticity, especially in penta- and heptafulvene, via the geometry-based “harmonic oscillator model of aromaticity”

Figure 10. (a) Dipolar resonance structures of pentafulvene. (b) Effect of substitution on the stability of the S0 and T1 states. Reproduced (adapted) with permission from ref 409. Copyright 2007 John Wiley and Sons. 3971


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those in the S0 state. By utilizing this property, one could easily predict the properties in the T1 state by varying the exocyclic substituents at the S0 state. The singlet−triplet energy gap can also be easily tuned by utilizing the “aromatic chameleon” property of fulvenes.409 This observation highlighted the fact that the first UV/vis absorption maxima of these species can be readily tuned by placing electron-withdrawing groups (EWGs) at the exocyclic position (case 1) and electron-donating substituents (EDGs) at the ring C atoms (case 2), thereby reducing the energy gap as compared to the parent pentafulvene. The effect is opposite, if groups of the opposite polarity are added (Figure 10b). The MP2 ab initio level of theory is useful in the study of tria-, penta-, hepta-, and nonafulvenes.410 For the global minimum structures, the occupation of the bonding π C−C orbital of the exocyclic C−C double bond quantitatively demonstrates πelectron delocalization. This can disclose partial 2-, 6-, and 10πelectron aromaticity, and 4-, 8-, and 12π-electron antiaromaticity of the ring moieties by NBO analysis. Williams and co-workers reported the synthesis of methylfulvene- and phenylfulveneannelated dihydropyrenes from cyclopentadiene-fused dihydropyrenes.411 From their ring-current measurements, the fulvenes showed distinct aromaticity when dihydropyrene is used as NMR probe, and the methyl- and phenylfulvenes were shown to be nonaromatic due to the bond localization induced in an aromatic system upon small-ring annelation (Mills−Nixon type effects) and the consequences of local anisotropies. The phenyl torsion angles for various fulvenes, such as the parent fulvene, diphenylfulvene, etc., were predicted by using geometry optimization calculations at the B3LYP/6-311+G(d,p) level and were in good agreement with the experimental spectral data.412 As mentioned earlier, numerous aromaticity indices have been suggested in the literature, which provide different orders of aromaticity.413,414 Therefore, to characterize the compounds, most theoretical chemists have recommended the use of a set of aromaticity indices based on different physical properties.415,416 As stated earlier, theoretical chemists have considered that aromaticity is reflected as a multidimensional physical phenomenon, which can be measured by a universal gauge that considers the different dimensions. In this context, Alonso and Herradon have expanded Kohonen’s self-organizing maps (SOMs) to a full set of organic molecules ranging from highly aromatic to highly antiaromatic, including fulvene.417 From their report, it can be concluded that the Euclidean distance (d) between neurons in the SOM is the first gauge of aromaticity conveyed in the literature, which includes the energetic, structural, and magnetic aspects of this phenomenon (multidimensional approach). This method helps us to find (1) the group (aromatic, nonaromatic, and antiaromatic) to which a compound belongs, (2) the extent of aromaticity/antiaromaticity, and (3) the similarity in aromaticity between different compounds. The aromaticity of pentafulvene is strongly reliant on the nature of the exocyclic substituent. A variation in the exocyclic position of the pentafulvene can perturb the system between the aromatic and antiaromatic extremes, depending on the electrondonating and -withdrawing power of the substituents (Figure 11).418 The aromatic and the antiaromatic character can be judged by prediction of fully advanced diatropic and paratropic ring currents through ab initio calculations performed at the ipsocentric 6-31G/CTOCD-DZ CHF level. Population shifts were inferred from the π electron density parameter, pEDA, which itself is found to correlate well with the empirical Hammett substituent constants.

Figure 11. Substituent effects in pentafulvene.

The electron affinities (EA) and ionization energies (IE) are intrinsic properties of the LUMO and HOMO, respectively. A computational investigation has established the substituent effects on the EAs and IEs of tria-, penta-, and heptafulvenes by considering the HOMOs and LUMOs of the compounds.419 The ionization energy decreases with EDGs and increases with EWGs. The range of electron affinities is wider than the range of ionization energies for pentafulvene with fixed exocyclic (variations for IE and EA are 1.60 and 2.42 eV, respectively) and endocyclic substituents (variations for IE and EA are 1.68 and 3.06 eV, respectively). Pentafulvenes can retain their aromatic resonance structure when they acquire one more electron, so they have higher EAs than tria- and heptafulvenes. The Shannon aromaticity (SA) index was also exploited for the prediction of substituent effects on the aromaticity of monosubstituted tria-, penta-, and heptafulvene derivatives.420 An assessment was made using the acquired SA values and a number of other aromaticity indices (HOMA, ISE, NICS(0), NICS(1), and NICS(1)zz). From these studies, it is clear that although NICS-based indices are not good enough to calculate the aromaticity of tria- and heptafulvene derivatives, the SA, ISE, and HOMA criteria are more dependable for this determination due to their good correlations with the calculated HOMO index. Subsequent reports showed how the excited-state aromaticity can be used as a device for regulating the excited-state energies for predicting the electron density distributions and photophysical properties in excited states at the IEF-PCM/TDB3LYP/6-311+G(d)//IEFPCM/B3LYP/6-311+G(d) level (Figure 12).421

Figure 12. Electron density distribution of fulvenes in the two states. Reproduced (adapted) with permission from ref 421. Copyright 2011 Royal Society of Chemistry.

Ottoson and co-workers provided insight into how aromaticity in the singlet ground state and the lowest triplet or quintet states affects the dipole moments and Natural Atomic Orbital (NAO) occupancies, as well as the shift of the overall π-electron density so as to accommodate, or to enrich, the aromaticity in each state.422 The effect of benzannulation in different fulvenes indicates the stabilization of pentafulvenes and destabilization of heptafulvenes in the triplet state. This also indicates that 3972


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Figure 13. Tautomeric equilibrium of 6-methylpentafulvene. Reproduced (adapted) with permission from ref 423. Copyright 2013 Springer.

electrostatic contributions favor cis complexes, and orbital contributions favor trans complexes. The computational chemist chooses different chemical properties for studying the performance of a molecule. Oziminski et al. selected CH···F complexation as a chemical property for studying the substituent effects of exo substitution at the 2- and 3positions of fulvene derivatives at the density functional theory level by using the Becke hybrid B3LYP functional with the 6311++G(d,p) basis set.426 From these calculations, one can clearly say that the substituent-dependent properties and the sensitivity of the ring hydrogen bonding are considerably higher for fulvenes than other benzene derivatives, and also that the 2position is more sensitive for fulvene than the 3-position. The influence of intramolecular hydrogen bonding on the geometry and electronic dimensions of pentafulvenes was explored by considering the multidimensional character of aromaticity using magnetic (NICS(0), NICS(1), and NICS(1)zz), geometrical (HOMA), and electronic (FLU and SA) principles.427 Hydrogen bonding acts as the aromaticity modulator in these cases, irrespective of the nature of the substituents on pentafulvene. From the above studies, it is clear that the hydrogen bonding predominantly influences the geometrical (HOMA) and electronic (SA) dimensions of aromaticity, rather than the FLU and NICS indices. In 2013, Oziminski studied the substituent effects of carboxylic fulvenes derivatives at the B3LYP/6-311++G (d,p) level of theory.428 Among the fulvene family, pentafulvene was the most sensitive to substitution. Because of the greater conjugation between the substituent and the carboxylic group in the 2position, the 2-substituted carboxylic derivatives display greater sensitivity to substituent effects than the 1-substituted derivatives (Figure 14).

benzannulation destabilizes the ground state and stabilizes the triplet state. This effect will be opposite in the case of heptafulvene, and is in line with the previously described “chameleon” behavior of fulvene. The thermodynamic and kinetic aspects of the tautomeric equilibrium of 6-methylpentafulvene and its exo-substituted derivatives were studied at the B3LYP/6-311++G(d,p) level of theory.423 In the case of CF3 and COCN, the exo methyl proton migrated to the endocyclic ring, and in substituted derivatives, I forms the most stable conformer, except in the case of CF3 and COCN, where II is the most stable form. The transition state activation energy for I is greater than that for II, and is raised by π-electron-donating groups and lowered by π-electron withdrawing groups, the −OH group being an exception due to the high aromaticity of the transition state. From the PCM (Polarizable Continuum Model) and SMD (universal solvation model based on solute electron density) methods, it is clear that solvent effects decrease the relative stability of the II tautomer for π-electron-donating substituents and raise its stability for a subset of π-electron-withdrawing ones (Figure 13). When forming complexes with alkali metals, pentafulvenes can show both equilibrium and nonequilibrium behavior. The aromaticity of these complexes in their equilibrium geometries (the charge transferred from metal to fulvene being close to one) was explored using different indices including geometry-based (HOMA), magnetism-based (NICS, NICS(1), and NICS(1)zz), p-electron count-based (pEDA), and electronic-based (Shannon aromaticity (SA)) indices.424 From the pEDA analysis, it is clear that the charge on the exocyclic carbon becomes more negative with the increase in the atomic radius of the metal atom, representing the weaker electrostatic attraction between the fulvene and the metal. All of these results are associated with each other and to some local and global properties. In the case of nonequilibrium complexes, the aromaticity indexes change with both the metal to fulvene distances and the binding energy. Complexes of alkaline earth metals with pentafulvenes tend to form the ansa-metallocene compounds with both singlet cis and triplet trans arrangements. Among these, almost all preferred η5 binding, except for beryllium. The stability, geometry, binding energy, degree of aromatization, and nature of bonding, etc., of these types of complexes were studied using different aromaticity indices, energy decomposition analysis of binding, and natural population analysis.425 From these studies, Oziminski concluded that aromatic stabilization of fulvenes arises because of the energy transfer from the metal. In these types of compounds, which contain a substantial contribution from covalent forms (Be, Mg, and Ca), the electrostatic contribution is dominant. Within this series of complexes, the total binding energy for the Mg complex is much smaller than anticipated, due to unbalancing between electrostatic and orbital interactions with the Pauli repulsion energy. While comparing the various contributions to the bonding of cis and trans complexes, it was demonstrated that

Figure 14. Carboxylic derivatives of pentafulvenes.

An extensive investigation into the π-bond delocalization of fulvenes has revealed that substituents have a strong influence on this property.24 7.2. Photophysical Properties of Pentafulvenes

The photophysical properties of organic molecules have been an electrifying field in the current scenario of organic electronics. The understanding of the excited-state properties aids in exploring the various behaviors of a molecule for constructing 3973


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predicted accurately from the degree of polarization of the planar structure. Later, in 1993, Galasso provided a reasonably comprehensive picture of the one- and two-photon electronic transitions of pentafulvene using the ab initio Random Phase Approximation (RPA) and Configuration Interaction (CI).433 One year later, Klessinger and Dreyer carried out semiempirical MNDOC-CI and ab initio complete-active-space self-consistent field (CASSCF) calculations for vertically and adiabatically excited states of planar and 90°-twisted fulvene.434 The twisting of the exocyclic double bond was studied using correlation diagrams as well as by calculating potential energy hypersurfaces. They also noticed that pyramidalization leads to a minimum in the triplet state, along with twisting to a conical intersection between the lowest two singlet states. In 1995, Jug and co-workers studied the low-lying excited states of fulvene by CI calculations using the SINDO1 (Symmetric Orthogonalized Intermediate Neglect of Differential Overlap) method.435 Structural optimization studies revealed that major reorganization in the ring geometry occurs in the excited state. The authors pointed out that there is an increase in the length of the exocyclic double bond in the lowest excited singlet S1 (1B2), while the endocyclic double bond is increased in the triplet T1 (3B2) state. The S1 (1B2) singlet state is moderately more aromatic than the T1(3B2) triplet states. Conical intersections between potential energy surfaces are now accepted as a key element in the photophysics and photochemistry of molecules.436−438 Information about how severe an ultrafast radiationless decay of a molecule will be, and whether a new product is formed or a reagent will degenerate, can be understood from the conical intersection of an excited state, and the topology of the potential surface, respectively. In fulvene, the first excited state is characterized by a fast internal conversion to the ground state via an S1/S0 seam of the conical intersection.434,439 In 2004, Bearpark and co-workers attempted to optimize the point on the conical intersection by introducing a geometric constraint. In this context, they established a second-order analysis for characterizing a stationary point in the degenerate space. 440 For further characterization of the seam, the optimization was modified by the conical intersection optimization algorithm based on projected gradients implemented in Gaussian. A constrained optimization in the space of the S1/S0 intersection was then executed to plot the seam of degeneracy at which the singlet excited state of fulvene experiences radiationless decay to the ground state at the CASSCF(6,6)/6-31G(d) level of theory.441 The constrained optimizations were carried out along (i) the methylene torsion coordinate, and (ii) the stretching coordinate of the C1−C6 bond. The radiation decay takes place at the seam of the intersection, which lies along a composite coordinate dominated by bond inversion and methylene torsion. If the photoisomerization between the cis and trans isomer is possible, and if there is any substituent on the ring and the methylene position, then the decay will be chemically relevant and is more rapid than the isomerization. This phenomenon occurs due to the fact that the initial relaxation direction in the excited state is orthogonal to the methylene rotation. Many conventional dyes lose their luminescence in their aggregated state due to the formation of excitons and excimers. However, in the case of certain molecules, this situation is not observed, and instead there is an increase in luminescence with aggregation; this is called aggregation-induced emission

laser dyes, probes, chemical sensors, and molecular switches. Various methodologies are accessible to study these photophysical processes, including theoretical and experimental methods. In 1981, Kent and co-workers studied the photochemistry of fulvene.429 Fulvene is characterized by a broad, weak, and diffuse S1 absorption band, corresponding to a valence excited state of B2 symmetry.430,431 From their studies, it was evident that no photochemical reaction occurred. These findings were supported by the diffuseness of the S1−S0 absorption. After vertical excitation to the S1(B) state, the ground-state fulvene is regenerated by an internal conversion mechanism, and no fluorescence was detected. The observed lack of fluorescence and diffuse spectral bands indicated a rapid radiationless decay to S0, and this was considered as the most likely deactivation pathway (Figure 15).

Figure 15. Kinetics and mechanisms of the photochemistry of fulvene. Reproduced (adapted) with permission from ref 429. Copyright 1981 American Chemical Society.

In 1990, Takahashi examined 90°-twisted structures of a variety of fulvenes and related compounds by open-shell and closed-shell SCF (Self Consistent Field) calculations with the semiempirical MINDO/3 (Modified Intermediate Neglect of Differential Overlap) approximation by assuming C2v symmetry.432 The authors focused mainly on (i) the relative stability of the singlet biradical and zwitterionic states (Figure 16) of the

Figure 16. Biradical versus zwitterion. Reproduced (adapted) with permission from ref 432. Copyright 1990 Elsevier.

90°-twisted structure, (ii) the relationships between the relative stability of the two states, and (iii) the molecular and electronic properties of the planar structure. For the parent fulvene, the biradical is 23.0 kcal/mol more stable than the zwitterion, while for 6,6-diaminofulvene, the zwitterion is more stable by 35.6 kcal/mol. In each case, solvent effects play a significant role in stabilizing the states. Electron-donating substituents at the exocyclic position can invert the relative stability of the two states. They also found that the two states have nearly degenerate energies, and that the relative stability of the two states can be 3974


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and signal processing, fledgling photonic technologies, data storage, optoelectronics, and photonics.451−455 The design of conjugate compounds with large second-order polarizability (or first-order hyperpolarizability, β) for second harmonic generation (SHG) has received much attention due to their nonlinear optical properties. This principle is used for the construction of highly nonlinear molecules by installing donors and acceptors in appropriate positions, capped with donor (D) and acceptor (A) moieties.456−460 A great deal of theoretical and experimental work has been carried out over the past two decades toward a complete understanding of the structure−property relationships of such compounds.461−463 Even though fulvenes are chemically different from common five-membered heterocycles such as pyrrole, thiophene, and selenophene, they have similar electronic structures; that is, they are valence isoelectronic. This has been attributed to the presence of the labile π electrons of the exocyclic CC double bond in fulvenes, which are similar to the π electrons provided by the heteroatom in five-membered heterocycles. The properties of a fulvene can be tuned by the appropriate placement of substituents.464 These features enabled the core to become functionalized materials with good conducting properties. By utilizing the tunability of the pentafulvene units, the band gap can be varied. If the value is below 1 eV, the molecule can be exploited for its conducting properties. Pentafulvene derivatives have been synthesized to better understand their electrochemical properties. For example, oligo6-(2-thienyl)pentafulvenes have been well studied.465 In this case, the 2-thienyl moiety offers two benefits: (1) electrondonating properties, which stabilize the dipolar structure of pentafulvene, and (2) a convenient site for metalation at the αposition, which provides a site for oligomer extension. Novel donor−π−acceptor chromophores have been developed on the basis of fulvene as an accepting moiety due to its higher polarizability,17 and 1,3-dithiole-2-ylidene as a donor moiety.466 One could readily make new dyes with a variety of solvatochromic effects and high hyperpolarizability by applying appropriately functionalized fulvenes with conjugating bridges. The chain length dependence studies of the excitation energies of oligomers of pentafulvenes were carried out by employing time-dependent density functional theory with the B3LYP functional.467 The band gaps and efficient conjugation lengths of the corresponding polymers were predicted by extrapolating the vertical excitation energies of their trimers through pentamers to infinite chain lengths. The reports suggested that PPf (polypentafulvene), PCp (polycyclopentadiene), Psi (polysilole), and PPh (polyphosphole) are appropriate candidates for novel conducting or optical materials because their band gaps are smaller than that of the well-studied PTh (polythiophene). The donor/acceptor strengths and the length of the conjugation path predominantly influence the molecular hyperpolarizability of a molecule. By examining this dependence for a selection of Λ-shaped molecules including fulvene, it was shown that fulvenes are promising candidates for constructing phasematchable SHG crystals, using the VB-2CT model.468 The VB2CT model turns out to be a simple and useful model for qualitatively describing the electronic component of the NLO properties. In 2010, Swager and co-workers prepared a series of 6,6-dicyanofulvene derivatives from masked, dimeric, or monomeric cyclopentadienones.41 The optical and electrochemical properties of 6,6-dicyanofulvene explicitly show that fulvenes are excellent candidates for organic electron transporters. By utilizing these resources, four new bis(pentafulvene)

(AIE).442 In this field, the photophysics of fulvene were further explored by constructing a propeller shaped fulvene derivative, which becomes highly emissive in the aggregated state in poor solvents.443 In contrast to the electronic effects, the steric effects or ring planarity dramatically alter the light-emitting behavior of the diphenyldibenzofulvene derivatives. Later, Blancafort and coworkers used the conical intersection model to describe this aggregation induced emission.444 Subsequently, a potential method for regulating population transfer was established, by altering either the initial geometry distribution or the initial momentum composition of the photoexcited wave packet.445 In both cases, the target of control is the force decay away from the default planar region toward the lower energy twisted area of the S1/S0 crossing seam, thereby switching off the stepwise population transfer. In 2011, Blancafort et al. studied the photodynamics of fulvene using a four-dimensional model including unreactive decay and double bond isomerization;446 the intramolecular vibrational energy redistribution (IVR) plays a significant role in this competition. In this context, the photodynamics of fulvene were described as a two-step and two-mode process. If IVR is slow, the excitation energy initially flows to the first mode, which leads to unreactive decay. Yet if the IVR is fast, decay along the second mode results in double bond isomerization. Later, a new mechanistic approach was established by the same group by shaping the topography of an extended seam of intersection with the nonresonant dynamic Stark effect (NRDSE) for adjusting the excited-state lifetime of fulvene.447 From their observations, it is clear that the extended nature of the seam is essential for stimulating and understanding the photophysics of organic molecules, especially for their lifetime control. As a photophysical application of fulvene, Bulovic and coworkers fabricated bulk heterojunction solar cells containing 6,6dicyanofulvenes as n-type additives.448 The correct choice and placement of functional groups resulted in fulvenes with properties comprising donor−π−acceptor behavior, intense absorption, and fluorescence. This behavior was elucidated by synthesizing and studying the structural and electronic properties of 1,3-diphenyl-6-alkyl/aryl-substituted fulvenes.194 However, in light of the subsequent review, the enormous impact of the excited-state aromaticity and antiaromaticity on the photophysical and photochemical properties has been extensively documented with the aid of computational modeling.449 More recently, studies by Diederich and co-workers have suggested that 6,6-dicyanopentafulvene has a very high potential for the construction of small electron-acceptor compounds with variable reduction potential.450 Here, the authors exploited the ability to create good electron-accepting moieties by altering the substituents using a range of computational and experimental methods. The presence and selection of electron-withdrawing groups influence the value of the reduction potential; for example, the highest experimental values (4.41 eV) were obtained for the 1,2,3,4-tetrachloro-6,6-dicyanofulvene and the 1,3,6,6-tetracyano-2,4-(p-NMe2-phenyl)fulvene. Computational studies have shown that values up to 5.29 eV, higher than that of F4-TCNQ (5.02 eV), might be obtained with even more electron-withdrawing substitution patterns. 7.3. Nonlinear Optical Properties

The linear and nonlinear optical properties (NLO) of molecules have attracted much attention from the scientific world by virtue of their latent applications in the areas of optical switching, optical data storage for the development of telecommunication 3975


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Present Addresses

dyes were prepared with a (fulvene)A−D−A(fulvene) design, with a variety of electron-rich cores.469 Recently, Ottoson and coworkers revealed how the HOMO−LUMO gap of poly pentafulvene and pentafulvene-based analogues can be tuned by exocyclic substitution, introduction of linker groups, benzannulation, and ring substitution, using results obtained at the PBC-B3LYP/6-31G(d) level.464 The substituent on the exocyclic position can be used to calibrate the electronic structure between quinoid and fulvenoid forms. They used bond length alternation (BLA) to discriminate between the two types. A positive value of BLA indicates the fulvenoid form, whereas a negative value suggests the quinoid form (Figure 17).

K. Syam Krishnan: Department of Chemistry, Mannam Memorial NSS College, Kottiyam (affiliated to the University of Kerala), Kerala, India Sreeja Thulasi: Department of Chemistry, T. K. Madhavan Memorial College, Nangiarkulangara (affiliated to the University of Kerala), Kerala, India Notes

The authors declare no competing financial interest. Biographies Mr. Preethanuj Preethalayam is a native of Karivellur (Kerala), India. In 2006, he graduated from Government College Kasaragod, Kannur University, majoring in chemistry, and from the same university received his masters degree in 2008. In May 2009, he moved to the CSIRNational Institute for Interdisciplinary Science and Technology, Thiruvananthapuram, as a research fellow. Later, in November 2011, he began doctoral research under the guidance of Dr. K. V. Radhakrishnan. The main focus of his thesis research is the synthetic utlization of pentafulvene and its derivatives using transition metalbased homogeneous catalysis.

Figure 17. Equilibrium between fulvenoid and quinoid forms. Reproduced (adapted) with permission from ref 464. Copyright 2015 American Chemical Society.

Dr. K. Syam Krishnan obtained his Ph.D. degree from the University of Kerala in 2008, under the supervision of Dr. K. V. Radhakrishnan (CSIRNIIST, Thiruvananthapuram). His doctoral work was mainly focused on the synthetic transformations of pentafulvenes. Later, he undertook postdoctoral research in total synthesis at the University of Jyvaskyla, Finland, with Prof. Petri M Pihko, and in organozirconium chemistry at the University of Reims, France, with Prof. Jan Szymoniak. After finishing his postdoctoral research in the field of bioactive ring fused 2pyridones at Umea University, Sweden, with Prof. Fredrik Almqvist, he took up a faculty position in the Department of Chemistry, Mannam Memorial NSS College, Kottiyam, affiliated to the University of Kerala in 2013. His research interests involve transition metal-free cycloaddition reactions, the development of novel BODIPYs, and green chemistry.

Electron-withdrawing substituents in the exocyclic position will lead to the polyfulvene to quinoid form, while those having electron-donating substituents will prefer the fulvenoid form. The BLA, which is related to the ground-state polarization, corresponds to the mixing of these limiting forms, and its value can be used to evaluate the NLO properties of such push−pull molecules.

8. CONCLUSION This Review provides a comprehensive account of the chemistry of pentafulvenes with special emphasis on their synthesis, cycloaddition chemistry, organometallic reactions, and calculated properties. The field of pentafulvene chemistry has experienced rapid growth over the past five decades, fueled by elegant work showcasing the unique reactivity of pentafulvenes in a plethora of cycloaddition reactions. These reactions have delivered a diverse array of novel carbo- and heterocyclic structures resembling important and ubiquitous natural product skeletons, in addition to serving as useful platforms for further transformations. Therefore, we envision that this Review, in addition to its didactic value, will serve to motivate organic chemists to expand the synthetic potential of pentafulvenes to afford libraries of novel, and structurally and biologically interesting, molecules. Although the growth of this area has been extraordinary, it still appears that there are many unexplored facets of pentafulvene chemistry, as evidenced by recent scientific activities. It is reasonable to assume that work on newer aspects of pentafulvenes will be highly rewarding.

Dr. Sreeja Thulasi is a native of Cherthala (Kerala), India. She obtained her M.Sc. degree in Chemistry from Sree Narayana College, Kollam (University of Kerala), in 2003. In 2011 she completed her Ph.D. in synthetic organic chemistry from the University of Kerala under the supervision of Dr. Luxmi Varma (CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram). Soon after, she took up a position as a project fellow in the group of Dr. K. V. Radhakrishnan where she worked on the dipolar cycloaddition of pentafulvenes and transformations using bis-π-allylpalladium complexes. She is currently Assistant Professor in Chemistry at T. K. Madhavan Memorial College, Nangiarkulangara (affiliated to the University of Kerala). Dr. S. Sarath Chand was born in Kerala, India. In 2006, he received his Bachelor of Science degree from Sree Narayana College, Punalur, and obtained his M.Sc. degree from Sree Narayana College, Kollam, in 2008. He then moved to the CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram, for his doctoral research under the guidance of Dr. K. V. Radhakrishnan. His Ph.D. work focused on Lewis acid/palladium-catalyzed synthetic transformations of pentafulvenes and their derivatives toward the synthesis of indole appended carbocycles and heterocycles. At present, he is a postdoctoral research fellow under the supervision of Prof. Charles Liotta at the School of Chemistry and Biochemistry of the Georgia Institute of Technology, Atlanta, GA.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: fl[email protected]. *E-mail: [email protected]. ORCID

Dr. Jomy Joseph was born in Kerala, India. In 2000, he graduated from Christ College, Calicut University, majoring in chemistry, and from the

K. V. Radhakrishnan: 0000-0001-8909-3175 3976


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the development of functional organic materials, dyes, and photochromic systems for use in a variety of applications.

same university received his masters degree in 2002. In November 2009, he obtained his Ph.D. degree in organic chemistry from IIT Roorkee under the combined supervision of Dr. Bir Sain, Prof. A. K. Jain, and Prof. R. N. Goyal. The main focus of his work was the development of new organic transformations using metal-based and metal-free catalytic systems. Thereafter, he spent one year as a postdoctoral researcher with Prof. Sukbok Chang, at the Korea Advanced Institute of Science and Technology, South Korea, where he developed C−N bond-forming reactions. He spent the subsequent two years as a postdoctoral researcher with Prof. Jan Szymoniak at the University of Reims, France, where his research was focused on titanium- and zirconium-based organic transformations. Currently, he is working with Prof. Herbert Waldmann and Dr. Andrey Antonchick at the Max Planck Institute for Molecular Physiology, Dortmund, Germany, where he is focused on developing enantioselective C−H bond activation reactions.

ACKNOWLEDGMENTS We thank the Council of Scientific and Industrial Research (12th FYP project, ORIGIN-CSC-0108), New Delhi, the Department of Science and Technology (DST), the Science and Engineering Research Board (SERB), New Delhi (SR/S1/OC-24/2014), and UGC for a research fellowship. Financial assistance from the Indo-French Centre for Promotion of Advanced Research (IFCPAR/CEFIPRA (Project 4505-1), is greatly acknowledged. REFERENCES (1) Hopf, H. In Cross Conjugation: Modern Dendralene, Radialene and Fulvene Chemistry; Hopf, H., Sherburn, M. S., Eds.; Wiley: New York, 2016; pp 1−440. (2) Neuenschwander, M. Fulvenes. In The Chemistry of Double-bonded Functional Groups; Patai, S., Ed.; John Wiley & Sons Ltd.: New York, 1989; pp 1131−1268. (3) Craig, D. P. Non Benzenoid Aromatic Compounds. In NonBenzenoid Aromatic Compounds; Ginsburg, D., Ed.; Interscience: New York, 1959; pp 1−42. (4) Krygowski, T. M.; Cyrański, M. K. Structural Aspects of Aromaticity. Chem. Rev. 2001, 101, 1385−1419. (5) Cyranski, M.; Krygowski, T. M. Separation of the Energetic and Geometric Contributions to Aromaticity. 3. Analysis of the Aromatic Character of Benzene Rings in Their Various Topological and Chemical Environments in the Substituted Benzene Derivatives. J. Chem. Inf. Model. 1996, 36, 1142−1145. (6) Wang, J. C.; Krische, M. J. Intramolecular Organocatalytic [3 + 2] Dipolar Cycloaddition: Stereospecific Cycloaddition and the Total Synthesis of (±)-Hirsutene. Angew. Chem., Int. Ed. 2003, 42, 5855− 5857. (7) Ohshima, T.; Kagechika, K.; Adachi, M.; Sodeoka, M.; Shibasaki, M. Asymmetric Heck Reaction-Carbanion Capture Process. Catalytic Asymmetric Total Synthesis of (−)Δ 9(12)-Capnellene. J. Am. Chem. Soc. 1996, 118, 7108−7116. (8) Revial, G.; Jabin, I.; Pfau, M. Enantioselective Synthesis of (+)-αVetivone Through the Michael Reaction of Chiral Imines. Tetrahedron: Asymmetry 2000, 11, 4975−4983. (9) Maulide, N.; Vanherck, J. C.; Markó, I. E. Connective Synthesis of Spirovetivanes: Total Synthesis of (±)-Agarospirol, (±)-Hinesol and (±)-α-Vetispirene. Eur. J. Org. Chem. 2004, 3962−3967. (10) Hu, Q. Y.; Zhou, G.; Corey, E. J. Application of Chiral Cationic Catalysts to Several Classical Syntheses of Racemic Natural Products Transforms Them into Highly Enantioselective Pathways. J. Am. Chem. Soc. 2004, 126, 13708−13713. (11) Goering, B. K.; Li, J.; Ganem, B. Aminocyclopentitols from Fulvenes: Syntheses of (+)-Trehazolin and the Pentasubstituted Cyclopentane of Keruffaride. Tetrahedron Lett. 1995, 36, 8905−8908. (12) Thiele, J. Ueber Ketonreactionen Bei Dem Cyclopentadiën. Ber. Dtsch. Chem. Ges. 1900, 33, 666−673. (13) Thiele, J.; Balhorn, H. Ueber Abkömmlinge Des Fulvens. 4. Condensationsproducte Des Cyklopentadiens. Liebigs Ann. Chem. 1906, 348, 1−15. (14) Day, J. H. The Fulvenes. Chem. Rev. 1953, 53, 167−189. (15) Bergmann, E. D. Fulvenes and Substituted Fulvenes. Chem. Rev. 1968, 68, 41−84. (16) Yates, P. Fulvenes. Advances in Alicyclic Chemistry; Academic Press: New York, 1968; Vol. 2, pp 59−184. (17) Zeller, K. P. Pentafulvenes. Methoden der Organischen Chemie 1985, 5/2c, 504−684. (18) Hafner, K.; Häfner, K. H.; König, C.; Kreuder, M.; Ploss, G.; Schulz, G.; Sturm, E.; Vöpel, K. H. Fulvenes as Isomers of Benzenoid Compounds. Angew. Chem., Int. Ed. Engl. 1963, 2, 123−134. (19) Alonso, M.; Herradon, B. A Universal Scale of Aromaticity for πOrganic Compounds. J. Comput. Chem. 2010, 31, 917−928.

Dr. G. Vijay Nair, born in October 1941 in Konni, Kerala, obtained his B.Sc.(Chem) degree in 1960 from the University of Kerala and his Ph.D. degree from BHU, Varanasi (1967), and the University of British Columbia, Canada (1969). He carried out postdoctoral work with Josef Fried (University of Chicago), Peter Yates (University of Toronto), and Gilbert Stork (Columbia University). He began his career as a Senior Research Chemist (1974) at the Lederle Laboratories of the American Cyanamide Co. and later became a Principal Research Chemist (1987). He joined Regional Research Laboratory (CSIR) Trivandrum as Deputy Director in 1990 and later became its Director (1997−2001). His research interests include the development of novel synthetic methodologies utilizing pentafulvenes as synthons, multicomponent reactions, NHC catalysis, allenes, cycloadditions, and transition metalcatalyzed organic transformations toward pharmaceutically important molecules. He has published more than 200 publications as senior author in major international journals, and 21 United States patents, many of which have worldwide coverage, and has guided 50 Ph.D. students. Dr. Florian Jaroschik obtained his M.Sc. in chemistry from Universität Regensburg, Germany, in 2004. For his Ph.D. studies, he moved to the Ecole Polytechnique in Palaiseau, France, where he worked under the supervision of Dr. François Nief in the field of low-valent organolanthanide chemistry. After two one-year postdoctoral positions at Monash University, Australia, with Profs. Glen Deacon and Peter Junk, and at the Université Pierre et Marie Curie, Paris VI, with Profs. Louis Fensterbank and Max Malacria, he joined the Institut de Chimie Moléculaire de Reims, France, as a CNRS Research Associate in November 2009. His current research interests concern the synthesis and applications of organometallic complexes of the lanthanides and group 4 metals. Dr. K. V. Radhakrishnan was born in Kerala, India. He received his B.Sc. and M.Sc. degrees from Christ College, Irinjalakuda, Kerala, India (University of Calicut). He obtained his Ph.D. degree in synthetic organic chemistry from the University of Kerala in 1998 under the supervision of Dr. Vijay Nair at CSIR-NIIST, Trivandrum. Subsequently he held postdoctoral positions at Tohoku University, Sendai, Japan, with Professor Yoshinori Yamamoto, at the Molecumetics Institute, Bellevue, WA, with Professor Michael Kahn, and at the NPG Research Institute, Raleigh, NC, with Professor Bert Fraser-Reid. He joined the National Institute for Interdisciplinary Science and Technology (NIIST-CSIR), Trivandrum, as a Scientist in the Chemical Sciences and Technology Division in May 2002. His research interests include the development of novel synthetic methodologies utilizing pentafulvenes as synthons, synthetic carbohydrate chemistry, transition metal-catalyzed organic transformations toward pharmaceutically important molecules, and phytochemistry with a focus on diabetes and cancer. In addition to the above, he is an active participant in a number of collaborative projects on 3977


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