# Transition-Metal Catalyzed, Thermally Driven [2π+2π]-Cycloadditions of Olefins and Alkynes

Leif E. Hertwig, Felix J. Becker, Dragos-Adrian Rosca

► To cite this version:

Leif E. Hertwig, Felix J. Becker, Dragos-Adrian Rosca. Transition-Metal Catalyzed, Thermally Driven [2π+2π]-Cycloadditions of Olefins and Alkynes. European Journal of Organic Chemistry, 2025, 28 (13), pp.e202401403. 10.1002/ejoc.202401403. hal-05042418

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# Transition-Metal Catalyzed, Thermally Driven $[2\pi+2\pi]$-Cycloadditions of Olefins and Alkynes

Leif E. Hertwig,*[a, b] Felix J. Becker,[a] and Dragoş-Adrian Roşca*[a, c]

The $[2+2]$-cycloaddition of olefins and alkynes stands out as a versatile and atom-economical strategy for synthesizing cyclobutane and cyclobutene building blocks, which are challenging to access through other synthetic methods. While photochemical approaches have traditionally dominated this field, thermally-driven methods employing transition metals offer distinct advantages, including decreased reliance on pre-

functionalized substrates and improved scalability. This review explores the underlying principles of metal-catalyzed $[2+2]$-cycloadditions and highlights recent advances in thermally-driven approaches for the efficient synthesis of cyclobutane and cyclobutene frameworks. Particular attention is given to electronically unbiased substrates, which remain a significant challenge for photochemical approaches.

## 1. Introduction

Cyclobutanes and cyclobutenes are important structural motifs found in numerous molecules relevant for the pharmaceutical industry. For example, drug discovery efforts have identified cyclobutane-containing molecules as promising therapeutic agents (see Figure 1) and this success has been translated in several drugs which are currently being commercialized[1,2] Structural features that make them attractive include a higher percentage of sp³-hybridized carbon atoms, conformational restriction and increased rigidity. The tridimensionality thus obtained allows a more efficient filling of a hydrophobic pocket, with a better control of the chemical space and directing key pharmacophores.[1,3] Fused rings based on cyclobutane and cyclobutene motifs can often function as aryl isosteres, enhancing solubility, altering binding affinities, and showing increased metabolic stability.[4,5] Due to their inherent ring strain compared to the larger ring analogues (cyclobutane 26.3 kcal/mol, cyclobutene 31–34 kcal/mol when referenced to cyclohexane),[6] cyclobutene rings can also function as synths for more complex molecules. Since they are prone to a thermodynamically downhill ring expansion, through bond reorganization and fragmentation, they can often lead to larger

<figure><img src="image_4.png" /><figcaption>Figure 1. Drug and drug candidates containing cyclobutane rings.</figcaption></figure>

rings and thus facilitate the total synthesis of a wide variety of organic molecules.[7,8]

Despite their net advantages over traditional building blocks, their use has been trailing the one of other strained rings (e.g. cyclopropyl).[9] A possible explanation for this is lack of available methods for their synthesis from readily available and inexpensive starting materials.

A privileged reaction pathway for accessing four membered rings (cyclobutanes and cyclobutenes) as part of more complex structures are the atom-economical $[2+2]$-cycloaddition reactions.

While such reactions are thermodynamically favored, under thermal conditions, they are symmetry-forbidden in accordance with the Woodward-Hoffmann rules.[10] Namely, due to conservation of symmetry, the wavefunction that describes the state of the interaction of two reactant molecules (olefins) correlates to the wavefunction that describes the doubly excited state (i.e. a state which cannot be coupled with the ground state *via* a single electron operator) of the product (cyclobutane) (i.e., red dotted line, Figure 2). It does not correlate with its ground state wavefunction. It is interesting to

<figure><img src="image_5.png" /></figure>

<footnote>[a] M.Sc. L. E. Hertwig, M.Sc. F. J. Becker, Priv.Doz. D.-A. Roşca
Anorganisch-Chemisches Institut
Universität Heidelberg
Im Neuenheimer Feld 276, 69120 Heidelberg, Germany
E-mail: dragos.rosca@uni-heidelberg.de</footnote>

<footnote>[b] M.Sc. L. E. Hertwig
Kjemisk Institut
Universitetet i Bergen, Bergen N-5007, Norway
E-mail: leif.hertwig@uib.no</footnote>

<footnote>[c] Priv.Doz. D.-A. Roşca
Institute des Sciences Chimiques de Rennes
Université de Rennes, F-35000, Rennes, France
E-mail: dragos-adrian.rosca@univ-rennes.fr</footnote>

<footnote>© 2025 The Author(s). European Journal of Organic Chemistry published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.</footnote>
<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /><figcaption>**Figure 2.** State correlation diagram for the prototype [2 + 2]-cycloaddition reaction (dimerization of ethylene). Dotted lines show the correlation of states with the same symmetry with respect to the symmetry planes of the transition state (mirror planes $σ_1$ and $σ_2$ depicted in inset). G.S = ground state, E.S. = excited state.</figcaption></figure>

point out that the reverse process, the retro-[2 + 2]-cycloaddition reaction, suffers from the same symmetry constraints in accordance with the principle of microscopic reversibility (black dotted line, Figure 2). Nevertheless, since the first excited

state of the starting materials correlates with the first excited state of the products (blue dotted line, Figure 2), photocatalytic approaches are symmetry-allowed. The latter approach represents indeed the most successful method to synthesize cyclobutanes from olefins,[11] which we will very briefly summarize in the 2nd chapter of this work.

A further interesting reaction class is represented by thermally driven [2 + 2]-cycloaddition reactions, an approach which mandates a *formal* lifting of the symmetry constrains without involving substrate or products excited states.

Normally this has been achieved by involving either d-orbitals or non-bonding p-orbitals in the transition state, which would have the right phase for efficient overlap (*vide infra*).

A very illustrative case here are the reactions between metal alkylidenes and alkenes to give 4-membered metallacycles, an elementary step in olefin metathesis reactions (Figure 3-B). In a similar fashion, metal carbynes are also capable of reacting with alkynes, to give even more unusual metalla-cyclobutadienes, which is an elementary step of catalytic alkyne metathesis.

A classical method of complying with the symmetry constraint is imposing a suprafacial-antarafacial orientation in the transition state. While this type of arrangement is not easily achievable for classical olefins due to the transition-state strain,[10] it can be achieved by ketenes due to the electrophilic character of the central carbon (i.e. formal presence of an orthogonal vacant p-orbital if one is to consider the vinylium resonance form) (Figure 3-C).[10] Interestingly, the activation barrier for this reaction is so low that it constitutes the most common reason for the instability of ketenes in the absence of bulkier substituents.[12] The same type of mechanism is proposed for the [2 + 2]-cycloaddition of ketenes with imines, which constitutes an important synthetic route for the synthesis of biologically relevant β-lactams.[11]

<figure><img src="image_8.png" /></figure>

Leif E. Hertwig obtained his B.Sc. in chemistry from the University of Heidelberg in 2019. In 2022 he obtained his M.Sc. in chemistry from the University of Heidelberg where he conducted his master thesis under the supervision of JProf. Dragoş-Adrian Roşca studying low-valent iron complexes and their application in [2 + 2]-cycloaddition reactions, synthesizing conformationally restricted bicycles. Currently he is carrying out his PhD work in the group of Prof. Vidar R. Jensen at the University of Bergen, Norway focusing on transition metal catalyzed nitrogen activation.

<figure><img src="image_9.png" /></figure>

Felix J. Becker received his B.Sc. in Chemistry in 2020 and the master degree in 2023 from the Ruprecht-Karls University of Heidelberg. His master thesis under supervision of JProf. Dragoş-Adrian Roşca focused on low-valent iron complexes in cycloaddition catalysis. In June 2024 he started his PhD at Philipps-Universität Marburg in the group of JProf. Alicia Casitas, focused on the isolation, structural and spectroscopic characterization and reactivity of high-valent iron metal complexes.

<figure><img src="image_10.png" /></figure>

Dragoş-Adrian Roşca obtained his PhD from the University of East Anglia in 2014, working under the supervision of Prof. Manfred Bochmann on gold(III) pincer complexes. Subsequently, he joined the group of Prof. Alois Fürstner at the Max-Planck Institut für Kohlenforschung, Germany as a postdoctoral Humboldt fellow. In 2018, he started his independent career at the University of Heidelberg, Germany obtaining his Habilitation in 2023 (chair of Prof. Lutz Gade), supported by the Fonds der Chemischen Industrie and the DFG. He is now a Junior Professor at the University of Rennes, France.
<figure><img src="image_11.png" /><figcaption>**Figure 3.** Approaches in non-photochemical formal [2 + 2]-cycloadditions.</figcaption></figure>

A suprafacial-antarafacial transition state arrangement has also been proposed in the [2 + 2]-cycloaddition of olefins with other cumulenes, such as isocyanates and allenes. Allenes typically require high temperatures (over 150 °C); however various transition-metal protocols have been able to significantly lower the activation barrier.[9] The latter approach allowed a better control of regioselectivity, also leading to improved yields; its usefulness is manifested in over 100 literature reports making use of allene-allene, allene-alkyne, and allene-alkene [2 + 2]-cycloadditions.[13,14]

Another method to enable thermally formal [2 + 2]-cycloaddition reactions is the use of metal species as mediators. The metal centers activate olefins either in a direct fashion, by functioning as π-philic centers, or indirectly, as Lewis acids which activate functional groups in conjugation with olefins. In is important to point out here that in this case, while the reaction outcome is a formal [2 + 2]-cycloaddition, mechanistically, these reactions proceed in a stepwise fashion, and are not concerted. In the case of Lewis acids (Figure 3-D), α,β-unsaturated ketones or esters, as well as enamines are often used as substrates, where the binding of the Lewis acid lowers the LUMO of the olefin, facilitating the interaction with the HOMO of the reaction partner and minimizing the Pauli repulsion between the reaction components.[15] Moreover, since the coordination of the Lewis acid induces charge polarization, this stabilizes the formation of a polarized intermediate, which ring-closes to the cyclobutane ring in a subsequent step. Due to the facile tunability of the steric environment around the Lewis

acid, this approach represents a particular synthetic advantage in achieving enantioselective [2 + 2]-cycloaddition (see Chapter 7).

The use of transition metals to activate C—C π-bonds can trigger oxidative cyclization followed by reductive elimination making use of two-electron redox steps. For these steps to proceed with high selectivity, late transition metals in low oxidation states are commonly used, and side-reactions such as β-hydride elimination or double bond migration need to be suppressed. In the case of [2 + 2]-cycloadditions involving alkynes, the intermediacy of metal-carbene intermediates has also been proposed.[16] An alternative reaction pathway involves one electron transfer reactions where the metal center transfers an electron to an olefin unit to generate a radical anion, which attacks a neighboring olefin, followed by ring closure (Figure 3-E).[17] The last two approaches summarized above (Figure 3, D and E) are particularly attractive since they allow, in principle a strong control over stereoselectivity. As they propose a different mechanistic pathway to bypass the orbital symmetry constraints, they are orthogonal to the better represented photochemical approaches.

## 1.1. Scope of this Review

The focus of this review therefore lies on methodologies briefly presented in Figure 3, D and E, which utilize transition-metal catalysts. Since this topic has been previously reviewed focusing on different aspects of these methodologies,[14,17–19] in this work, special attention will be given to unactivated and electronically unbiased substrates, which are regarded to be particularly challenging for the photocatalytic approach. Thermally-allowed cycloaddition reactions which can be further optimized with the aid of transition-metal catalysis (i. e. involving the transformation of cumulenes) fall outside of the scope of this review. Where primary data allow it, the mechanistic investigations (either by experimental or computational means) will be summarized in order to establish common patterns of reactivity.

## 2. Brief Overview of Photochemical [2 + 2]-Cycloadditions Between Alkenes

Since the most established method to achieve cyclobutanes is the photochemical [2 + 2] cycloaddition, a brief summary will be given to illustrate the differences to the thermally-activated cyclizations. This topic has been reviewed extensively.[9,11,17,20–25]

As illustrated in Figure 2, the ground state of two weakly interacting olefins is correlated with a doubly excited state of the cyclobutane product. In contrast, the first excited state of the starting materials correlates with the first excited state of the cyclobutane product, implying that a photochemical approach is not energetically prohibitive to achieve this transformation.
<figure><img src="image_12.png" /></figure>

Since the first observation in 1877 by Liebermann,[26] this technique has evolved into a useful tool for organic synthesis. Nevertheless, in practice, for unactivated olefins, the excitation energy required is often significantly high, rendering this method less practical. Several strategies have been used to circumvent this problem: (a) the use of conjugated π-systems which induce a red-shift of the absorption maximum compared to isolated unsaturated bonds; (b) η²-coordination to metal complexes, which enforces a pre-organization for the cyclization and induces a red-shift in the absorption maximum (e.g. the Cu-based Salomon-Kochi reaction, see Figure 4);[27] (c) the use of a photosensitizer (e.g. acetone, benzophenone, acetophenone), which undergoes energy transfer to the olefin subsequent to excitation;[11] (d) by using a metal complex or an organic dye, which upon excitation can transfer a single electron to the olefin (a process described as photoinduced electron transfer (PET) or, in modern literature, photoredox catalysis).[11] Recent developments have yielded a library of photosensitizers and photoredox catalysts which absorb longer wavelengths of light (UV-A and visible light) significantly enhancing the functional group tolerance of such approaches.[17,28–30]

<figure><img src="image_13.png" /><figcaption>**Figure 4.** Photochemical [2 + 2]-cycloaddition reactions: concept and selected strategies. S = Singlet, T = Triplet, ISC = Intersystem crossing.</figcaption></figure>

A challenge is suppressing homodimerization reactions, and hence, the excited state of the alkene needs to be long-lived to compensate for the substrate diffusion and Pauli repulsion. α,β-unsaturated enones or α,β-unsaturated carboxylic acid derivatives (Figure 4-B) typically have long lifetimes in the excited state and, due to the conjugated nature of the double bonds, require less harsh conditions for reactivity. It is therefore not surprising that they have been privileged motifs for this reaction. For example, 2-cyclopentenones with a stereogenic center in the 4-position have recently been studied by the groups of Aitken,[31,32] Carreira,[33] Corey[34,35] and Lange,[36,37] as part of total synthesis campaigns, in the context of bioactive compounds (e.g. Hippolachnin A, Figure 1; Antheliolide A[38–40]).

A further recent improvement is the combination of visible light excitation with Lewis acid catalysis, yielding even higher (enantio)selectivities[17] and a better modular development of the methodologies.[41,42]

An intrinsic constraint of photochemical methods is the reliance on substrates which have a narrower separation between the ground state and the first excited state, often colloquially, though not strictly correctly - referred to as a narrow HOMO-LUMO gap. This characteristic dictates a certain pre-functionalization of the starting materials, and therefore simple, unconjugated olefins are considered challenging substrates. In recent years, though innovative approaches (e.g. modification of the Kochi-Salomon reaction, photoredox catalysis) this has been successfully addressed (see for example Figure 4-D).[43,44] Despite these impressive synthetic advances, the practical limitations of photochemical methods persist for large-scale, long-term applications. These challenges are primarily related to scalability, reliance on cost- and energy inefficient UV light sources, and the necessity of designing flow reactors to address the inverse square law constraints of light propagation. Even with recent advancements, the development of such reactors remains highly complex, non-trivial, and requires individual optimization for each specific reaction.[45,46]

## 3. Transition-Metal Catalyzed [2+2]-Cycloadditions of Alkenes

### 3.1. [2+2]-Cycloaddition Between Alkenes and Dienes

An early example for the [2 + 2]-cycloaddition of two alkenes is the titanium-catalyzed cyclization of ethylene and 1,3-butadiene (Scheme 1), marking the first catalytic cyclodimerization, to

<figure><img src="image_14.png" /><figcaption>**Scheme 1.** First example for the cyclodimerization of ethylene and 1,3-butadiene to form VCB catalyzed by homogeneous Ti-complexes.</figcaption></figure>
<figure><img src="image_15.png" /></figure>

<figure><img src="image_16.png" /><figcaption>**Scheme 2.** Early example of Ni(0)-catalyzed [2 + 2]-cycloaddition of 1,3-butadiene.</figcaption></figure>

form vinylcyclobutane (VCB) 1 in good yield (75%) but relying on forcing temperatures and high pressures.[47]

The addition of donor ligand 1,10-phenanthroline maximizes the yield of VCB by suppressing competing side reactions, such as C=C isomerization and the formation of 1,4-hexadiene via co-dimerization. Strained olefins, norbornene and norbornadiene (NBD), could also successfully be cyclized with 1,3-butadiene to afford the cyclobutane products in yields up to 90%.[47] In the presence of Ni(COD)₂, tris(2-biphenyl)phosphite, and 1,3-butadiene undergoes [2 + 2]-cycloaddition. When the 1,3-butadiene was not fully consumed, cis-1,2-divinylcyclobutane 2 is obtained with yield up to 40% (Scheme 2).[48–50] The lower yield could be explained by competing side reactions such as Ni-catalyzed and thermal Cope-rearrangement, to form 3.

## 3.2. [2+2]-Cycloadditions Using Strained Olefins as Substrates

Since the first reports of transition-metal catalyzed dimerization of norbornadiene (NBD) emerged more than 50 years ago, numerous examples emerged employing low oxidation-state nickel, iron, cobalt and rhodium complexes, yielding a mixture of dimerization products (Scheme 3).[51–54] The use of strained substrates (norbornadiene derivatives) has since become one of the more prominent strategies for transition-metal catalyzed [2 + 2]-cycloadditions of two alkene moieties under thermal conditions.

Norbornadiene and many electron-deficient alkenes undergo homo [2 + 2 + 2]-cycloaddition in the presence of Ni(0)-catalysts. However, in certain cases, alkenes, such as methyl-enecyclopropane 4 selectively undergo [2 + 2]-cycloaddition with norbornadiene to selectively yield the *endo*-product 5 in

<figure><img src="image_17.png" /><figcaption>**Scheme 3.** Transition-metal catalyzed dimerization of norbornadiene to form various dimerization products.</figcaption></figure>

<figure><img src="image_18.png" /><figcaption>**Scheme 4.** Low-valent Ni-catalyzed [2 + 2]-cycloaddition of NBD and methyl-enecyclopropane.</figcaption></figure>

86% yield (Scheme 4).[55] The *endo*-selectivity is enforced by the bidentate coordination of norbornadiene to the nickel center.

Strained *exo*-cyclopropyl norbornene 6 and benzo-derivative 8 also readily undergo [2 + 2]-cycloadditions with electron-deficient olefins achieving high *exo*-selectivity and stereoselectivity with respect to the substituents on the olefins 7 and 9 (Scheme 5a–b).[56,57] The [2 + 2]-cycloaddition is highly sensitive towards geometrical changes at the remote side of the norbornenes and norbornadienes and, as proposed by Noyori, homoconjugation between the C=C-bond and the benzene or cyclopropane is crucial for facilitating bonding interactions between the C=C-bond of norbornadiene, the alkene, and the nickel-catalyst, therefore lowering the transition state of the metallacycle formation.[56]

The reaction between substituted norbornadienes (e.g. 10) and highly reactive enophiles (e.g. N-phenyl maleimide 11) exclusively undergo [2 + 2]-cycloaddition with high regioselectivity albeit low stereoselectivity (Scheme 5c–d).[57] In the case of electron-deficient 2,3-disubstituted 10 the *exo*-[2 + 2] adduct 12

<figure><img src="image_19.png" /><figcaption>**Scheme 5.** Various examples for the Ni(0)- and Rh(1)-catalyzed [2 + 2]-cycloaddition of strained NBD derivatives affording highly substituted cyclobutane derivatives.</figcaption></figure>
<figure><img src="image_20.png" /></figure>

(49%) is formed exclusively, while the electron-rich 2-substituted analogue **13** forms yields preferentially the *endo*--[2+2] adduct **14** (*endo*: *exo* ratio 12:1, 69% yield).

Cationic Rh(I)-complexes were also reported to be active in the intermolecular [2+2]-cycloaddition of tricyclic olefins with dienes to afford the cyclobutane **16** in moderate yield (36%, Scheme 5e). Mechanistically, the cycloaddition is proposed to proceed through coordination of the rhodium to the *exo*-face of **15** followed by the formation of a metallacycle. The cycloaddition products of norbornene and norbornadiene are generally formed with excellent *exo*-selectivity which is rooted in the non-planarity of the π-system of the bicyclic alkene, leading to an increased π-electron density on the *exo*-face compared to the *endo*-face. While this effect is weak, it is sufficient to induce the stereoselective [2+2]-cycloaddition where the cyclic alkene is preferably coordinated on the *exo*-face.[58,59] The vinylcyclobutane **16** is released through subsequent reductive elimination. Only traces of [2+2+2]-cycloaddition product are observed.[60]

### 3.3. Intramolecular [2+2]-Cycloaddition

The first intramolecular metal-catalyzed [2+2]-cycloaddition of bis-enones was reported by Krische *et al.* (Scheme 6).[61] The reaction relies on a acetylacetonato-derived cobalt catalyst and is highly dependent on the choice and equivalents of silane. 2.4 equiv. of phenylsilane additive gives exclusive rise to the Michael cyclo reduction product **18**. Nevertheless, the [2+2]-cycloaddition products **17, 19–22**, could be obtained in excellent yields (69–72%) and as single stereoisomers, by employing 4 equiv. of phenylmethylsilane, therefore efficiently suppressing the cyclo reduction (<11%). Heteroatom-linked (O, NTs) bis-enones also undergo [2+2]-cycloaddition readily (**19** and **20**). Furthermore, diastereoselectivity could be directed when using siloxy-substituted bis-enones yielding **21** as a single stereoisomer (65%). Further substrates include mixed bis-enones containing aliphatic and aromatic substituents as well as heteroaromatic bis-enones giving moderate yields of the [2+2]-adducts, such as the 2-furyl substituted cyclobutane **22**.

<figure><img src="image_21.png" /><figcaption>**Scheme 6.** Co-catalyzed [2+2]-cycloaddition of bis-enones.</figcaption></figure>

<figure><img src="image_22.png" /><figcaption>**Scheme 7.** Condition dependent, alkylation-cyclization or [2+2]-cycloaddition of bis-enones catalyzed by Gilman cuprates.</figcaption></figure>

Mechanistic studies suggest the [2+2]-cycloaddition proceeds *via* metallo-oxy-π-alkyl and transition metal anion radical species, formed through electron-transfer-mediated enone reduction.[62] Bis-enones also undergo [2+2]-cycloaddition through $Me_2CuLi$ catalyzed outer-sphere electron transfer (ET) (Scheme 7). The Gilman reagent serves as an ET reagent to form a distonic anion radical intermediate which further undergoes [2+2]-cycloaddition to form the cyclobutane-based product. ET to the bis-enone substrate **23** initiates the anion radical chain reaction. Control of the cuprate equivalents, rate of addition, and concentration determine the selectivity towards the alkylation product **24** or the [2+2]-product **25**.[63] The ET can also be facilitated by arene anion radicals or cathodic reduction.[63,64]

Gansäuer *et al.* reported a method to achieve a broader substrate scope through the $Cp_2Ti(III)(TFA)_2$-catalyzed [2+2]-cycloaddition protocol for bis-enones, which proceeds *via* an inner-sphere electron transfer (Scheme 8).[65] In contrast to the previously reported Co-catalyzed [2+2]-cycloaddition of bis-enones, this methodology also tolerates substrates with two alkyl substituents and cyclobutanes **26–30** were obtained in high yields (74–90%) throughout. Nitro-substituents are readily reduced leading to catalyst deactivation. Essentially, all products were obtained as a single stereoisomer (d.r. >99:1) except **26** and **27** where slightly lower d.r. values of 96:4 were observed. DFT calculations suggest that the reaction proceeds through an initial inner-sphere electron transfer to the enone

<figure><img src="image_23.png" /><figcaption>**Scheme 8.** Ti-catalyzed [2+2]-cycloaddition protocol of bis-enones.</figcaption></figure>
<figure><img src="image_24.png" /></figure>

(A) followed by a 5-exo cyclization (B) (Scheme 8, right). Subsequent 4-exo cyclization of the enoyl radical forms the titanocene enolate (D) after which the product is released, regenerating the Ti(III)-catalyst.

### 3.4. A Special Case: The Use of Redox-Active Ligands for the [2+2]-Cycloaddition of Olefins for Iron and Cobalt Catalysis

#### 3.4.1. Concept, Mechanism, Ligand Design

A powerful methodology for [2+2]-cycloadditions was introduced by Chirik in 2006, employing an iron-catalyzed approach (Scheme 9).[66] This method enables the conversion of unactivated alkenes into their corresponding cyclobutanes under relatively mild conditions. Notably, substrates, such as small alkenes, unconjugated dienes, allylic amines, and ethers – typically incompatible with traditional photochemical methods – are well-suited to this approach. Consequently, this methodology is orthogonal to conventional strategies, which often rely on ring strain, Lewis acids, or electron-withdrawing groups to lower the LUMO and thereby enhance the reactivity of unsaturated C–C bonds.

The mechanism is thought to follow a coordination-oxidative cyclization–reductive elimination sequence, involving net two-electron redox steps (Scheme 9). While this type of sequence is typically associated with the more noble late transition metals (4d and 5d), it is far less common for 3d transition metals, where single-electron transfer processes are more prevalent. A defining aspect of the herein described approach is the use of pyridinediimine (PDI) (e.g. 31, 32) scaffolds which allow active participation of both the ligand and the metal center in the redox elementary steps. Over time, the mechanistic understanding has been refined through insights gained from kinetic studies, spectroscopic techniques (NMR, Mössbauer), crystallographic analyses, and computational investigations. Species which support this mechanism, such as η²-iron olefin complexes 33 or iron metallacycles 34 have been

characterized via crystallographic methods (Scheme 9).[67] While a conceivably deleterious step is the post-cyclization β-hydrogen elimination, this pathway seems to be suppressed, probably due to the involvement of high-spin states along the reaction trajectory.

Computational modeling of the reaction trajectories and isolated intermediates, using both DFT and ab initio (CASSCF) methods, aligns with a two-state reactivity mechanism.[68–70] According to these studies, the oxidative cyclization step proceeds on a triplet potential energy surface, whereas the reductive elimination occurs on an open-shell singlet surface, highlighting the distinct electronic states involved in each stage of the reaction. This type of reactivity further highlights the potential of spin-unrestricted species, allowing a greater flexibility for the distribution electron density in challenging elementary steps.

In parallel with advances in mechanistic understanding, a variety of low-valent iron-based scaffolds (31, 32, 35–39) featuring redox-active, non-innocent pyridine-based PDI ligands have been developed (Scheme 10).[48–52] These scaffolds have not only facilitated a more systematic exploration of the reaction mechanism but have also enabled the mapping of electronic and steric effects critical for designing highly active catalysts.

Amongst the elements of ligand design directly correlated with catalytic activity, the nature of the steric bulk of the N-flanking groups and the nature of the heterocyclic ring appear to play an important role. The π-acidity of the supporting heterocyclic ring determines the conversion rate and catalyst stability. Both the diazine isosteres, the pyrimidine-diimine (P<sup>Pym</sup>DI) 40 and pyrazine-diimine (P<sup>Pz</sup>DI) scaffolds have been tested in the [2+2]-cycloaddition of olefins by Roşca<sup>[70]</sup> and Chirik,[71] respectively. Both systems perform slower than the parent pyridinediimine variants, which are less π-acidic. However, the P<sup>Pym</sup>DI scaffolds 40 have proven to be significantly more stable and less susceptible towards deactivation as indicated by the kinetic profile of the [2+2]-cycloaddition of (Scheme 11) while the (PDI)Fe(N<sub>2</sub>)<sub>2</sub> analogue undergoes deactivation in the first reaction half-life.[70] The stability is rationalized by the more electron-deficient nature of the catalyst, which prevents the formation of intramolecular iron olefin complexes, a known deactivation pathway for PDI-systems.[71] Electronic

<figure><img src="image_25.png" /><figcaption>**Scheme 9.** Fe-mediated intramolecular [2 + 2]-cycloaddition using unactivated olefins: excerpt of substrate scope, mechanistic proposal and isolated intermediates.</figcaption></figure>

<figure><img src="image_26.png" /><figcaption>**Scheme 10.** Selection of low valent iron pre-catalysts for [2 + 2]-cycloadditions.</figcaption></figure>
<figure><img src="image_27.png" /><figcaption>**Scheme 11.** Kinetic profiles of different iron-based cycloaddition catalysts differing by the nature of the supporting heterocyclic ring and by the steric bulk of the flanking groups. The most active catalyst is highlighted in the grey inset.</figcaption></figure>

fine tuning of the ligand by introducing electron-donating substituents in the *para*-position of the flanking groups, as well as bulky cyclopentyl groups in the 2,6-position of the aryl groups (40) leads to a significant increase in the reaction rate.

As discussed above, increasing the bulk of the flanking groups enhances the rate of the intramolecular [2 + 2]-cycloaddition, regardless of the specific nature of the heterocyclic ring involved.[70,71] The size of the flanking groups is thought to play a role in accelerating the reductive elimination step, therefore suppressing deleterious β-hydrogen elimination or olefin isomerization pathways.[72]

### 3.4.2. Substrate Scope

The present iron-catalyzed method tolerates both intramolecular as well as intermolecular [2 + 2]-cycloaddition reactions, and various catalyst variants derived from the iron-PDI-blueprint have been tailored to suit either of the two variants.

**Intramolecular [2+2] cycloaddition.** In the case of intramolecular [2 + 2]-cycloaddition reactions, using PDI-based iron catalysts, strained cyclobutane-containing hydrocarbons as well as the benzyl-protected aza-bicyclo[3.2.0]heptane were synthesized in high yield with catalyst loadings between 5–10%, while employing a Boc protecting group lead to low isolated yields (24%) even at higher catalyst loadings (10 mol% catalyst, Scheme 9).[66,72] For the synthesis of cyclobutane rings fused with cyclic amines of various ring sizes, pyrimidinediimine iron systems of type 40 have demonstrated remarkable versatility. As such, strained motifs containing pyrrolidine-, piperidine-, and azepane- motifs could be synthesized in excellent yields, and usually using low catalyst loadings (1 mol%) (Scheme 12). Interestingly, the stereochemistry of the ring formed is dictated by its ring size: while cyclobutane-functionalized pyrrolidine and piperidine adopt a *cis*-configuration, the 7-membered ring analogue is formed exclusively as the *trans*-configured product. For racemic α-substituted amines, ring-closure proceeds with moderate diastereoselectivity, which is dependent on the size of the α-substituent. Since the synthesized motifs are bioisosters of other *N*-heterocycles, their potential downstream functionalization is essential: in this respect, the method tolerates easily removable protecting groups (e.g. Boc), or alternatively, a

<figure><img src="image_28.png" /><figcaption>**Scheme 12.** Synthesis of cyclobutane-fused *N*-heterocycles, using pyrimidine-diimine-based iron catalysts.</figcaption></figure>

protocol for the removal of tosyl groups has been demonstrated.[70]

**The intermolecular [2+2]-cycloaddition** of unactivated olefins is a particularly attractive method since it allows the synthesis of specialized cyclobutane-containing building blocks from readily available (even biosourced) olefins. To the best of our knowledge, the only method that can achieve this without relying on UV-A light is by using iron catalysis.[72,73] The reaction usually yields a *cis*-configured cyclobutane as a single stereoisomer. Low catalyst loadings (1 mol%) could be maintained for simple hydrocarbon or pyrrole-functionalized substrates, but conversion of substrates containing Lewis-basic sites (e.g. furans) was more challenging (Scheme 13). A competing reaction pathway, *β*-hydrogen elimination, could be suppressed by increasing the steric bulk of the flanking groups and of the *α*-imino substituents at the ligand backbone.[73]

The methodology could be then be subsequently applied to the oligomerization of butadiene, in some cases, using catalyst loadings as low as 0.2 mol%.[74] The resulting telechelic 1,3-enchained cyclobutane-containing oligomers of different molecular weights could be separated due to their difference in solubility properties. Remarkably, the iron-catalyzed [2 + 2]-cycloaddition is reversible under vacuum and elevated temperatures. This leads to net deoligomerization and reforms the hydrocarbon feedstocks. The deconstruction of vinylcyclobutane 41 allowed for almost quantitative recovery of the butadiene (94%) as well as 75% of the ethylene, while in case of 1,5'-(divinyl)polycyclobutane 42 partial deoligomerization is achieved.[74]

Apart from olefin homocoupling, heterocoupling of simple olefins with 1,3-dienes has been achieved at low catalyst loadings (Scheme 14).[75] The most efficient catalyst system is an iron allyl complex (43) obtained by the reaction of ethylene with an iron η⁴-butiene complex. This loaded complex also represents an on-cycle catalytic intermediate, and can undergo reductive elimination to release the cyclobutane-functionalized cross-dimerized product.[75,76] Apart from simple olefins, various silane and stannane functionalized olefins can also undergo this
<figure><img src="image_29.png" /></figure>

<figure><img src="image_30.png" /><figcaption>**Scheme 13.** Homocoupling in [2 + 2]-cycloaddition: dimerization of unactivated olefins, oligomerization of 1,3-dienes and vacuum-induced depolymerization of cyclobutane-functionalized polymers.</figcaption></figure>

transformation.[77] Other key pre-catalysts which can be employed in this type of transformations are iron methyl species[78] or iron η⁴-butadiene complexes based pyrazinediimine scaffolds.[71] While simple butadiene undergoes this reaction smoothly, 2,3-dimethyl-1,3-butadiene proved to be challenging, and in the case of isoprene, the formal 1,4-addition of ethylene to butadiene, to yield (E)-2-methylhexa-2,4-diene was observed. This competing pathway could be suppressed by employing a more rigid ligand backbone, obtained by tethering the α-imino alkyl groups to the pyridine heterocycle (44), which further accelerated reductive elimination and suppressed β-hydrogen elimination.[73]

This iron-based methodology for the heterodimerization of olefins with conjugated dienes is complementary to one mediated by Ti- or Ni-based catalysts (Scheme 1 and 2).[47–50]

Although most research on [2 + 2]-cycloadditions with redox-active ligands has centered on iron, cobalt analogues (e.g. 45, 46) also exhibit high catalytic activity and offer a complementary substrate scope compared to their iron counterparts (Scheme 15).[79] A noteworthy class of substrates tolerated by the cobalt-based systems are allyl ethers, which are challenging with iron PDI complex, probably due to C–O bond cleavage.

# 4. Transition-Metal Catalyzed [2+2]-Cycloadditions Between Alkenes and Alkynes

## 4.1. [2+2]-Cycloadditions of Strained Olefins and Alkynes

In a similar fashion to alkene-alkene [2 + 2]-cycloaddition (Chapter 3), the use of strained norbornene and norbornadiene derivatives has become the most prominent approach in alkene-alkyne [2 + 2]-cycloaddition. This highly versatile tool allows access to a vast chemical space of substituted cyclobutenes with over 100 examples reported in the literature, employing Ru, Ni, Co, Rh, Re, or Ir catalysts (Scheme 16 and 17). As previously mentioned, the cycloaddition of norbornene and norbornadiene generally proceed to form the exo-products. Mechanistically, the reactions are generally thought to proceed via a metallacycle intermediate, subsequently releasing the corresponding cyclobutene after reductive elimination (Scheme 16, top right). Not surprisingly, the [2 + 2]-cycloaddition of unsymmetric cyclic olefins and unsymmetrical alkynes, such as trimethylsilyl acetylene, afford a mixture of two regioisomers arising from the different coordination orientations of the alkyne moiety.[80]

The first reported example of transition metal-catalyzed [2 + 2]-cycloaddition between norbornenes and dimethyl acetylene
■ General cross-[2+2]-cycloadditions

<figure><img src="image_31.png" /></figure>

Via:

<figure><img src="image_32.png" /></figure>

43

**Selected Examples**

- Olefin/isopren-[2+2]-cycloadditions

<figure><img src="image_33.png" /></figure>

- Vinylsilane/piperylene-[2+2]-cycloadditions

<figure><img src="image_34.png" /></figure>

■ [2+2]-cycloadditions of α-olefines and isopren derivatives

<figure><img src="image_35.png" /></figure>

**Selected Examples**

<figure><img src="image_36.png" /></figure>

<figure><img src="image_37.png" /></figure>

<figure><img src="image_38.png" /><figcaption>**Scheme 14.** Heterocoupling in [2 + 2]-cycloaddition: reactions of olefins with 1,3-conjugated dienes.</figcaption></figure>
<figure><img src="image_39.png" /></figure>

<figure><img src="image_40.png" /><figcaption>**Scheme 15.** Intramolecular [2 + 2]-cycloaddition mediated by Co-based PDI systems.</figcaption></figure>

<figure><img src="image_41.png" /></figure>

<figure><img src="image_42.png" /></figure>

<figure><img src="image_43.png" /></figure>

<figure><img src="image_44.png" /><figcaption>**Scheme 16.** Transition metal catalyzed [2 + 2]-cycloaddition of NBD and norbornene derivatives and alkynes.</figcaption></figure>

<figure><img src="image_45.png" /><figcaption>**Scheme 17.** Enantioselective Ir-catalyzed [2 + 2]-cycloaddition of substituted norbornadiene derivatives.</figcaption></figure>

dicarboxylate in the presence of catalytic amounts of [H₂Ru(PPh₃)₄] was reported in 1976 by Mitsudo *et al.*, to form the *exo*-tricyclo[4.2.1.0.2<sup>5</sup>].non-3-ene-3,4-dicarboxylate **47** in 87% yield.[81,82] Subsequently, Ru-complexes have grown to be one of the most versatile tools in this transformation with numerous reports utilizing various Ru(0) and Ru(II) catalysts at temperatures between 25 and 100 °C, allowing to access a vast chemical space with over 90 reported tricylic cyclobutenes. Only a few selected examples **47–51** (Scheme 16, [Ru]) will be discussed here.[81–103] The use of terminal alkynes primarily leads to the formation of cyclotrimerization products.[87]

Tam *et al.* reported the [2 + 2]-cycloaddition of bridgehead-substituted norbornadienes with ethyl 3-phenylpropiolate, in the presence of catalytic amounts of Cp*RuCl(cod), yielding the *anti*-exo cycloadducts as the only regio- and stereoisomer, in good yields (Scheme 16, **48**, 89%).[104] Generally, a significant decrease in reactivity was observed with more electron-deficient alkenes, dictated by the bridgehead substituent (OAc < OTBS < H < Hex < Ph). Tam *et al.* also studied alkyl phosphonates as substrates for the Ru-catalyzed [2 + 2]-cycloaddition to give the corresponding products in varying yields (Scheme 16, **49**, 36%).[100] Dimethyl, diethyl and diphenyl substituted phosphonates were also tolerated. In the presence of Cp*RuCl(cod), acylic ynamides bearing an electron-withdrawing substituent (CO₂Me, SO₂Tol) readily underwent [2 + 2]-cycloaddition with norbornene (Scheme 16, **50**, 83%). Chiral cyclic ynamides also underwent [2 + 2]-cycloaddition in good yields (60–83%) albeit only showing low diastereoselectivity (ca. 72:28).[96] A protocol for the asymmetric [2 + 2]-cycloaddition of norbornenes and norbornadiene derivatives with alkynes employed alkynes bearing a chiral acyl camphosultam auxiliary, achieving high stereo- and regioselectivity and showing excellent ee of up to 66:1 (Scheme 16, **51**) after the reductive removal of the chiral auxiliary.[92,102]

Glockner *et al.* reported the first Ni-catalyzed [2 + 2]-cycloaddition (2 mol% Ni(CN)₂(PPh₃)₂) of norbornadiene with diphenylacetylene at 120 °C to form 7,8-diphenyltricyclo[4.2.1.0.2<sup>5</sup>].nona-3,7-diene in 59% yield (Scheme 16, **52**). Other active Ni-catalysts include Ni(cod)₂ and Ni(CO)₄. Alkynes with a stronger degree of activation, such as diethyl acetylene dicarboxylate, did not undergo [2 + 2]-cycloaddition but rather formed [2 + 2 + 2]-homo-Diels-Alder-addition products.[105] Cheng *et al.* reported the [2 + 2]-cycloaddition of oxabenzonorbornadienes and azabenzonorbornadienes with alkynes in presence of Ni(PPh₃)₂Cl₂, PPh₃ and Zn in toluene at 52–90 °C, forming the *exo*-cyclobutenes (Scheme 16, **53**) in good yields (42–98%). The outcome of the catalysis depends on the reaction conditions with monosubstituted alkynes undergoing mostly [2 + 2 + 2]-cyclotrimerization at ambient temperatures and [2 + 2]-cycloaddition dominating at 80 °C. Under vacuum, at temperatures of 500 °C, the [2 + 2]-cycloaddition products readily underwent ring expansion, forming the corresponding 8-membered carbocycles.[106] Cheng *et al.* reported a Co-based catalytic system consisting of Col₂(PPh₃)₂ (5 mol%), PPh₃ (16 mol%), and Zn powder which catalyzes the [2 + 2]-cycloaddition of oxabenzonorbornadienes and azabenzonorbornadienes with alkynes at 90 °C, affording the corresponding
<figure><img src="image_46.png" /></figure>

cyclobutenes in moderate to excellent yields (30–95%). In contrast to the Ni-based catalyst, a variety of previously incompatible alkynes are tolerated, including terminal acetylenes (54) and dialkyl acetylenes (55). The rate of the background reaction, the [2 + 2 + 2]-cyclotrimerization, was found to be low.[80] Based on this work, Hilt *et al.* developed the [2 + 2]-cycloaddition of norbornenes with internal alkynes catalyzed by Co(dppp)Br₂ (dppp = 1,3-Bis(diphenylphosphino)propane) forming the cyclobutene derivatives in excellent yields (Scheme 16, 54–57, 51–99%).[107] In contrast to the catalytic system reported Cheng *et al.*,[80] this methodology does not yield any norbornene dimerization products and therefore, no excess of substrate or extra phosphine addition is needed to suppress such side reactions. Symmetric as well as unsymmetric alkyl/aryl-substituted alkynes are tolerated (56, 98%) and even bicyclo[2.2.0]hept-3-enes bearing an aldehyde moiety in 1-position can undergo [2 + 2]-cycloaddition with excellent yields (57, 90%).

Using a chiral Rh-H<sub>8</sub>-BINAP catalyst, Kawachi *et al.* synthesized chiral cyclobutenes via [2 + 2]-cycloaddition of norbornene derivatives and alkylpropiolates and arylpropiolates (Scheme 16, 58–60) in good to excellent yields (55–99%) and moderate to high enantioselectivities (55–99% ee).[108] At higher temperatures benzonorbornadiene also underwent cyclization (Scheme 16: 61–62).[108] Moreover, mixtures of [ReBr(CO)<sub>3</sub>(thf)]<sub>2</sub> and isocyanide additives were catalytically active for the cyclization of norborne, norbornadiene and benzonorbornadiene with both internal and terminal alkynes in moderate to good yields (17–92%, Scheme 16: 63–64).[109]

Iridium-catalyzed enantioselective [2 + 2]-cycloaddition was also reported, using (R)-Xylyl-phanephos as a chiral ligand.[110] Namely, oxabicyclic alkenes can undergo cycloaddition with terminal alkynes (Scheme 17: 65, 66), forming four stereocenters with good to excellent enantioselectivity (98–99% ee). In a follow-up study, the kinetic resolution of racemic C1-substituted oxabenzonorbornadienes by Ir-catalyzed [2 + 2]-cycloaddition was reported, employing the same catalytic system.[111] In contrast to the previously discussed examples (Scheme 16), mechanistic studies suggest that the catalytic cycle proceeds through a hydrido(acetylene)iridium(III) complex formed upon oxidative addition of the acetylene (A). (Scheme 17, right). After an exo-selective migratory insertion (B) into the C=C bond (B). Reductive elimination forms the hydro alkynylation product with Subsequent reinsertion (C) followed by reductive elimination (D) produces the [2 + 2] cycloaddition product 66.[112]

## 4.2. Intermolecular [2 + 2]-Cycloadditions Using Less Strained Substrates

An early example for intermolecular [2 + 2]-cycloaddition of an olefin and alkyne was reported by Scheck *et al.* It consists of the synthesis of substituted bicyclo[3.2.0]heptenes and octenes via [2 + 2]-cycloaddition catalyzed by cyclopentadienyldicarbonyliron complex 67 (Scheme 18). However, the methodology relies on substoichiometric catalyst loadings (50 mol%) and is limited

<figure><img src="image_47.png" /><figcaption>**Scheme 18.** Fe-catalyzed [2 + 2]-cycloaddition of cyclopentene/cyclohexene with methyl propiolate.</figcaption></figure>

<figure><img src="image_48.png" /><figcaption>**Scheme 19.** Co-catalyzed [2 + 2]-cycloaddition and competing alder-ene reaction of internal alkynes and cyclic olefins.</figcaption></figure>

to methyl propiolate and cyclopentene or cyclohexene as substrates. 1,2-Disubstituted cyclic or acyclic olefins gave ca. 1:1 mixtures of cyclobutene and 1,3-dienes while other olefins were underwent lactonization.[113]

A more versatile approach was developed in 2008 by Treutwein *et al.* and represents the first Co-based method for the [2 + 2]-cycloaddition of cyclopentene. It relies on the same catalytic system used the [2 + 2]-cycloaddition of strained bicyclic norbornadiene derivatives (Scheme 16), namely using Co(dppp)Br₂, in situ activated with a mixture of Zn/ZnI₂. Cyclobutenes 69a–71a, 73a were obtained in moderate to excellent yields (23–99%) while selectively forming the exo-product (Scheme 19).[107,114] The methodology tolerates heterocycles (70) and 1,3-diynes (71a, 73a) with varying selectivity towards the [2 + 2]-cycloaddition affording alder-ene sideproduct depended on the alkyne substituents (16–74%). Bulky 1,2-bis(trimethylsilyl)acetylenes and cyclohexene remained unreactive under the presented conditions. Both the choice of alkyne and supporting bis-phosphine ligand affect the selectivity of the [2 + 2]-cycloaddition reaction. Ligands exhibiting lower bite angles, alkynes bearing oxygen in the propargylic position, and more generally the use of cycloheptene favoured the alder-ene adducts as the major products.

During their investigations on the Pd-catalyzed bromoalkynylation of norbornene, Zhou *et al.* observed that in the presence of catalytic amounts of Pd(OAc)₂ and a bromoalkyne, the more flexible cyclooctene underwent [2 + 2]-cycloaddition to form the corresponding bicyclo[6.2.0]decene 74–76 (Scheme 20).[115] Aromatic alkynyl bromides bearing both electron-donating (75) and electron-withdrawing substituents (74) are tolerated, but the latter afforded the [2 + 2]-product only in low yields (15%). Iodoalkynes also underwent [2 + 2]-cycloaddition in good yield (73%) to give 76. On the other hand, norbornene did not undergo [2 + 2]-cycloaddition but rather
<figure><img src="image_49.png" /></figure>

<figure><img src="image_50.png" /><figcaption>**Scheme 20.** Pd-catalyzed [2 + 2]-cycloaddition of haloalkynes and cyclooctene.</figcaption></figure>

bromoalkynylation to forming the corresponding 2-bromo-7-alkinyl)-bicyclo[2.2.1]heptane. In analogy to the Co-catalyzed methodology by Treutwein *et al.*, [114] cycloheptene predominantly afforded the alder-ene by-product. Less strained cyclooctene showed no reactivity towards [2 + 2]-cycloaddition.[115]

In 2018, RajanBabu *et al.* reported the formal tandem [2 + 2]-cycloaddition/hydrovinylation reaction between 1,3-enynes and ethylene catalyzed by bis-phosphinic cobalt complexes granting access to vinylcyclobutenes or cyclobutantes (Scheme 21-a). [116] Short reaction times and low temperatures selectively yielded the cyclobutene products from [2 + 2]-cycloaddition reaction (Scheme 21a) while longer reaction times at room temperature exclusively gave rise to the hydrovinylation products as mixture of isomers (Scheme 21-b). Catalysts based on bis-phosphines (e.g. 77) turned out to show especially high activity. In contrast to previous protocols, (Schemes 16–20) there is no prerequisite for the use strained alkenes and optimized activation of the Co(II)-precatalyst with Et₂AlCl was key to the good yields (>60%) of cyclobutanes 80–89. The functional group tolerance was limited to alkyl (82, 87), cycloalkyl (80, 85), alkene (81, 86) and aromatic (84) substituents, owed to the excess of alkyl aluminum reagent used in the activation process. Terminal alkynes did not undergo subsequent hydrovinylation. Additionally, this methodology allows to control the addition of another ethylene molecule to the [2 + 2]-products in an enantioselective manner where the best enantioselectivities were achieved with the chiral phosphinooxazoline ligands (e.r. >91:9, 78 and 79).

An improved version of the enantioselective [2 + 2]-cycloaddition was reported shortly after, demonstrating enhanced substrate tolerance (Scheme 22). This method enabled the synthesis of over 50 different cyclobutenes with good to excellent yields and enantioselectivities ranging from 86% to 97%.[117] Chiral phosphinooxazoline ligands 90 or 91 proved to be the best performing ligands and the Co(II)-precatalyst is activated *in situ* by Zn and Na[B(3,5-CF₃-C₆H₃)]₄ (Scheme 22).

While the previous approaches made use of *in-situ* activated of pre-catalysts, Chirik *et al.* employed a well-defined cationic [(dppf)Co(η⁶-C₇H₈)][BArF₄] precatalyst for the [2 + 2]-cycloaddition of 3-hexyne derivatives and ethylene, which yielded the cyclobutene derivatives in excellent yields (> 92%). [118] Despite the fact that the reaction needs to be run under inert conditions, the precatalyst can be weighed out under air. The methodology tolerates both carbonylic- and boronic esters (92–95), but is limited to internal alkynes. Mechanistic investigations support a pathway where the cationic Co(I) species facilitates

<figure><img src="image_51.png" /><figcaption>**Scheme 21.** Co-catalyzed [2 + 2]-cycloaddition of 1,3-enynes and ethylene optionally followed by enantioselective hydrovinylation.</figcaption></figure>

<figure><img src="image_52.png" /><figcaption>**Scheme 22.** Enantioselective Co-catalyzed [2 + 2]-cycloaddition of internal alkynes and alkenyl derivatives.</figcaption></figure>

oxidative cyclization forming an intermediate Co(III)-metallacycle. Subsequent reductive elimination releases the respective cyclobutene (Scheme 23, bottom). A mechanism where the cationic Co-complex acts as a π-Lewis acid, analogous to Au(I)-catalyzed [2 + 2]-cycloadditions (*vide infra*) was ruled out due to

<figure><img src="image_53.png" /><figcaption>**Scheme 23.** Intermolecular [2 + 2]-cycloaddition of internal alkynes with ethylene catalyzed by a cationic Co(I)-arene complex.</figcaption></figure>
<figure><img src="image_54.png" /></figure>

lacking reactivity of the more sterically hindered isobutylene and cis-2-butene substrates. When using propylene as substrate, competing β-hydride elimination from the metallacycle affords a 1:1 mixture of cyclobutene and acyclic product (Scheme 23, bottom). Deuterium labelling experiments ruled out a mechanism proceeding *via* Co-hydride intermediates and are consistent with the proposed Co-metallacycle.[118]

The synthesis of cyclobutenes (97a–99a), catalyzed by [Rh(OH)(cod)]₂, from electron-deficient olefins 96 and diphenylacetylene in good yields was reported by Baba *et al* (Scheme 24).[119] In all cases, Mizoroki-Heck-type ene-yne coupling products 97b–99b (9–27%) were formed as side products. While the mechanism of the reaction was not further studied, two possible pathways were proposed, both of which proceed through an unsaturated Rh–H species.

The previously herein discussed methodologies are limited to the use of internal alkynes. While the Au(I)-catalyzed [2 + 2]-cycloaddition of styrenes with aliphatic alkenes has previously been reported by Echavarren *et al*. (vide infra, Chapter 7),[16] Kakiuchi *et al*. developed the first intermolecular [2 + 2]-cycloaddition of terminal and electron-deficient alkynes catalyzed by an 8-quinolinalato rhodium/phosphine system (Scheme 25).[120] The 1,3-subsituted cyclobutenes 100–105 were obtained as single regioisomers in varying yields (26–99%).

While studying ynamide arylations, Lam *et al*. discovered that in the presence of [Rh(C₂H₄)₂Cl]₂ and a racemic diene rac-106, the aryl- and alkyl-substituted oxazolidinone-based ynamies 107 undergo [2 + 2]-cycloaddition with nitroalkenes to form the corresponding cyclobutenamides 109–113 in good yields (Scheme 26).[121] Efforts to render the reaction enantioselective remained unsuccessful and in all cases a mixture of diastereomers were obtained. While in case of aryl-substituted ynamides (109–112), the diastereomers could be separated,

<figure><img src="image_55.png" /><figcaption>**Scheme 26.** Rh-catalyzed intermolecular [2 + 2]-cycloaddition of oxazolidione-based ynamides and nitroalkenes.</figcaption></figure>

alkyl-substituted ynamide 113 gave an inseparable mixture of diastereomers.

Another methodology, developed by Ogoshi *et al*. utilizes catalytic mounts of Ni(cod)₂ and di-iso-propylphenyl)imidazol-2-ylidene (IPr) for the [2 + 2]-cycloaddition of conjugated enynes and enones to obtain the cyclobutenes 114 in good yields and high chemo- and regioselectivity (Scheme 27). The scope includes substrates bearing bulky substituents (115), vinyl-phosphonates (120), lactones (119), and cyclohexenones (118). In the case of cis- or trans-5-phenyl-2-penten-4-yne, the corresponding (Z)-117 and (E)-118 cyclobutenes are obtained in a selective manner, showing no signs of isomerization. During the mechanistic studies, the authors have isolated of a key reaction intermediate: the first (η³-butadienyl(nickel) complex (Scheme 27, right). This intermediate arises a enone coordination of the to the Ni(0) and subsequent oxidative addition form the isolated nickelacycle, followed by reductive elimination forms the cyclobutene product. The η³-coordination suppresses deleterious reaction pathways, such as [2 + 2 + 2]-cycloaddition.[122] Albeit electronically-neutral, alkenes such as 1-decene also undergo cyclization, to afford an 1:1: mixture of stereoisomers.

<figure><img src="image_56.png" /><figcaption>**Scheme 24.** Rh-catalyzed [2 + 2]-cycloaddition of diphenylacetylene with electron-deficient alkenes.</figcaption></figure>

<figure><img src="image_57.png" /><figcaption>**Scheme 25.** Rh-catalyzed [2 + 2]-cycloaddition of terminal alkynes with electron-deficient alkenes.</figcaption></figure>

<figure><img src="image_58.png" /><figcaption>**Scheme 27.** Ni(0)-catalyzed intermolecular [2 + 2]-cycloaddition of conjugated enynes with electron-deficient olefins.</figcaption></figure>
<figure><img src="image_59.png" /></figure>

### 4.3. Intramolecular [2+2]-Cycloadditions

Fürstner *et al.* discovered that iodinated enynes are readily cyclized in the presence of catalytic amounts of [Cp*Ru(MeCN)₃]PF₆ at ambient conditions using DMF as solvent.[123] The corresponding cyclobutene-functionalized bi-cycles (123–134) could be isolated in good to excellent yields (60–94%, Scheme 28). Enynes tethered by an ether (124–126), amide (127, 129–130) or a methylene fragment (128) are tolerated with both aliphatic or aromatic backbones and even tricyclic cyclobutenes are accessible. Generally, electron-rich substrates turned out to be preferred in this transformation and electron-poor substrates, such as nitro-substituted enynes resisted cyclization. The reaction is proposed to proceed *via* a metallocycle (122) intermediate subsequently releasing the cyclobutene after reductive elimination. For reasons to be further elucidated, cyclobutenyl iodide (123) were obtained in excellent yield while the corresponding bromide (125) gave slightly lower yield and the chloride was gave no conversion (126). Similarly, internal or terminal alkynes remained unreactive.

While studying the cycloisomerization of enyneamides, Plietker *et al.* discovered that exposing *N*-allyl propargyl acetates to the redox neutral cationic Fe complex 135 did not lead to the formation of the allene *via* cycloisomerization but rather afforded the azabicyclo[3.2.0]heptane 136 in 71% yield (Scheme 29).[124] The methodology proceeds in moderate to

good yield (30–79%) and tolerates esters, amides and halides as well as different propargylic esters such as phenylacetates (137–139), cinnamates and sorbates. Propargylic amides underwent cyclization with low regioselectivities (ca. 2:1) while a homopropargylic amide afforded the corresponding azabicyclo[4.2.0]octane (140) as a single isomer. DFT calculations backed the mechanistic proposal (Scheme 29, right). In their proposal the authors state that the cationic Fe complex initially coordinates the alkyne and releases one PPh₃. A stepwise 1,2-acyloxy migration (A and B) leads to a Fe-carbene species. Subsequent [2+2]-cycloaddition with the adjacent alkene (C) forms a metallacyclobutane intermediate. 1,2-acycloxy migration (D) and reductive elimination (E) release the azabicyclo[3.2.0]heptane 136. For internal alkenes, the cycloisomerization of the enyne acetate is preferred and the corresponding allene is observed.[125]

To obtain mechanistic insight of the intermolecular alkyne/alkene coupling, Fürstner *et al.* subjected the 4-hydroxyenyne 141 towards catalytic amounts of the [Cp*RuCl] catalyst (Scheme 30).[126] At low temperatures in THF-*d*₈, intermediate 142 could be isolated and characterized by NMR and single crystal X-ray diffraction revealing a chiral tetrahedral Ru center with a strong hydrogen bonding between the OH group and the chloride of the ruthenium. 142 marks the first isolated ruthenium complex bearing an enyne ligand. While the bond lengths suggest a significant degree of activation, stericities mediated by the methyl group prevents oxidative cyclization taking place at low temperatures. At ambient temperatures in CD₂Cl₂, the cyclobutene is formed quantitatively by oxidative cyclization, presumably *via* the metallacycle 143. Subsequent reductive elimination and isomerization yields the corresponding cyclobutene derivative 144.

In context of 1,6-enyne metathesis, Trost *et al.* proposed a mechanism proceeding *via* an elusive, highly strained cyclobutene formed through [2+2]-cycloaddition. However, enynes with a longer chain length (145) readily underwent intramolecular [2+2]-cycloaddition in the presence of catalytic amounts of a Pd catalyst and tri-*o*-tolylphosphite at elevated temperatures in DCE (Scheme 31, right).[127] The formed trans-fused 8/6 tri-cycle (146) could be isolated in 85% yield. In the case of cyclohexene-containing 1,7-enyne 147 the opposite stereoselectivity is observed, yielding a cis-fused 6/6 fused ring 148 (Scheme 31, left).

<figure><img src="image_60.png" /><figcaption>Scheme 28. Ru-catalyzed formal [2+2]-cycloaddition of 1-haloenynes.</figcaption></figure>

<figure><img src="image_61.png" /><figcaption>Scheme 29. Fe-catalyzed [2+2]-cycloaddition of 1,6- and 1,7-enyneacetates.</figcaption></figure>

<figure><img src="image_62.png" /><figcaption>Scheme 30. Intramolecular, hydroxy-mediated Ru-catalyzed [2+2]-cycloaddition of a 1,6-enynehydroxide.</figcaption></figure>
<figure><img src="image_63.png" /></figure>

<figure><img src="image_64.png" /><figcaption>Scheme 31. Pd-catalyzed intramolecular [2 + 2]-cycloaddition of 1,7-enynes.</figcaption></figure>

## 5. Transition-Metal Catalyzed [2+2]-Cycloadditions Between Two Alkynes

The [2 + 2 + 2]-cyclotrimerizations of acetylenes to benzene derivatives by various transition metals,[128,129] including Co,[130] Fe,[131] Ni,[132] Rh,[133] Pd,[134] and the formation of η⁴-cyclobutadiene complexes are well documented. While the noble-group metals, including Pt (149),[135] and Rh (150),[136] readily facilitate [2 + 2]-cycloaddition of alkynes forming η⁴-cyclobutadiene complexes (Scheme 32),[137] the corresponding complexes of Co, Fe, Ni, and other 3d-transition metals are usually not formed via dimerization of two alkyne moieties but the η⁴-cyclobutadiene fragment is rather introduced by transmetalation with a platinum-group η⁴-cyclobutadiene complex.[138,139]

Examples of alkyne-alkyne [2 + 2]-cycloadditions which form cyclobutenes are scarce, since the formation of the corresponding metal η⁴-cyclobutadiene complexes represent a thermodynamic

sink, hindering catalytic turnover even under forcing conditions.[136] Two approaches can be distinguished here, which will be briefly summarized below: (i) stoichiometric approaches, usually relying on Ru, Zr and Cu, which mandate the hydrolysis of the formed metal η⁴-cyclobutadiene complexes and (ii) catalytic approaches, based on nickel catalysis.

Stoichiometric approaches rely on Ru-, [140] Cu-, [141] and Zr-cyclobutadiene complexes (Scheme 32 and 33)[142] One such example was reported by Itoh *et al.* where the alkyne dimerization affords the Ru-η⁴-cyclobutadiene complex 151 which, after hydrolysis, affords cyclobutene 152 in excellent yield (90%).[140] Tilley *et al.* demonstrated that Zr-cyclopentadiene 153, bearing bulky substituents in α-position w.r.t. zirconium on the cyclopentaliating fragment, enable oxidative transmetallation to afford the dimeric, formally Cu(III)-metallacyclopetadiene 154. Thermally-induced reductive elimination quantitatively yields the phenanthrocyclobutadiene 155.[141] This approach presents a novel approach which grants efficient access to phenanthrocyclobutadiene like 155. This class of compounds show interesting optical and electrochemical properties as organic electronic materials. In the absence of the transmetallation to copper, the hydrolysis of Zr-cyclopentadienes, such as 153, with HCl would have otherwise yielded the corresponding diene.[143] In the context of the synthesis of polycyclic aromatic hydrocarbons, Gade *et al.* reported the synthesis of the doubly cyclobutene-annulated tetraazacoronene 158 via cyclization of diyne 156. The approach, previously introduced by Tilley *et al.*[144,145] used in situ reduced Cp₂ZrCl₂,[146] in the presence of trimethylsilyl (TMS)-substituted diyne 156 (Scheme 32).[142] In

<figure><img src="image_65.png" /><figcaption>Scheme 32. Transition-metal mediated dimerization of internal alkynes forming η⁴-cyclobutadiene or cyclopentadiene complexes.</figcaption></figure>

<figure><img src="image_66.png" /><figcaption>Scheme 33. Zr-mediated [2 + 2]-cycloaddition of alkynes for the synthesis of tetrasubstituted trans-cyclobutenes.</figcaption></figure>
<figure><img src="image_67.png" /></figure>

contrast to previous literature approaches, which yield Cp₂Zr cycloendiadienes under these conditions (for example **153**), the authors could isolate a rare example of a Cp₂Zr- η⁴-cyclobutadiene complex **157**, which crystallises as a the coordination polymer. No active light irradiation was used in this approach, in contrast to the only other precedent of this type of reactivity reported by Milsmann *et al.*, who relied on the irradiation of a Zr-dibenzyl complex at 462 nm in the presence of diphenylacetylene.[147] Hydrolysis of **157** using acetic acid formed the azacoronene **158** in moderate yield (30% over two steps).[142]

While studying the stoichiometric reaction between Cp₂ZrBu₂ and heteroaryl-substituted alkynes, Song *et al.* reported that upon hydrolysis by water, tetrasubstituted cyclobutene derivatives **159–162** were formed in yields of 28–88% (Scheme 33).[148] In all cases, the cyclodimerization proceeds in high regio- and stereoselectivities to exclusively afford the *trans*-products with a head-to-tail pattern regarding the heteroaryl-substituted alkynes. Aryl alkynes, alkyl alkynes and 2-thienylalkyne as well as 3-pyridylakyne resisted cyclodimerization indicating that the nitrogen-containing heterocycles, with the correct positional isomerism are essential. The authors propose that the mechanism involves the formation of an unsymmetrical Zr-cyclopentadiene complex **163** in which the heteroaromatic moiety coordinated to the metal center. Subsequent reductive elimination formed a *N*-donor stabilized η²-cyclobutadiene complex **164** which released the cyclobutene **165** when quenched with water. This mechanistic proposal is in line with the observed selectivity.

**A catalytic approach** for the [2 + 2]-cycloaddition of alkynes was reported by Pericàs *et al.* using a reductive Ni-mediated approach. The method grants access to various tetrasubstituted head-to-tail *trans*-cyclobutenes in excellent regio- and stereoselectivities and moderate yields (Scheme 34),[149] and, to the best of our knowledge, remains the only non-light driven catalytic approach for the [2 + 2]-cycloaddition of two alkynes. Extensive functional group tolerance could be demonstrated, and alkynes bearing aryl with electron-donating or withdrawing groups (167–169), alcohols (170), different heterocycles (171–172) underwent cyclization. Even more complex molecules, such as steroid derivatives could be employed in heterocou-

pling reactions with 1-phenyl-1-priopin, to afford the cyclobutene **173** in 59% yield. No homocoupling of two steroid precursors occurred, probably due to steric bulk. Hammett analysis revealed positive charge accumulation in the transition state of the turnover limiting step (p < 0) and kinetic isotope effect (KIE) experiments are consistent with Ni(II)-metallacycle **174** as the catalytic resting state, formed after oxidative cyclization (Scheme 34, right).

## 6. Radical Cation-Induced [2+2]-Cycloadditions

Electron rich olefins readily engaged in [2 + 2]-cycloaddition mediated by radical cation-induced methodologies.[150] The first radical-cation catalyzed cyclodimerization of *N*-vinylncarbazole, catalyzed by Fe(III) and Ce(IV) salts, was reported in 1969 by Ledwith *et al.*[151] Since then, a variety of other initiation methods have been reported, including hypervalent iodine reagents, photoredox catalysts (e.g. based on Ru, Cr, Ir, Ti), as well as electrochemical methods.[150] In the context of transition metal-mediated reactions without light, iron catalysis dominate the field. In 2001, Nakamura reported the cyclodimerization of *trans*-anethole **174** using alumina supported Fe(ClO₄)₃ as a one-electron oxidant, achieving exclusive stereoselectivity, and forming the C₂-symmetric anti-substituted cyclobutane **175** (Scheme 35).[152] Interestingly, the use of chiral bisoxazoline (box) ligands (10 mol%, Scheme 35, right) failed to provide sufficient enantioselectivity as **175** was obtained with a maximum of 7% ee. Mechanistically, it was proposed that the reaction proceeds *via* a single electron oxidation of **174** and subsequent, stepwise, cyclization to form cyclobutane **175**.

Using Fe(ClO₄)₃ hexahydrate as catalyst, an expanded substrate scope of cross-[2 + 2]-cycloaddition between anet-holes and substituted styrenes to give alkyl-substituted (176, 58%) or fluorinated cyclobutanes (177, 60%) was later reported by Zhong *et al.* (Scheme 36).[153] While the reaction readily proceeded in degassed solvent, oxygen had a beneficial effect on the catalytic performance indicating it as a possible re-oxidation agent for reduced Fe(II) to boost the reaction progression.

<figure><img src="image_68.png" /><figcaption>**Scheme 34.** Highly regio- and stereoselective Ni-catalyzed intermolecular [2 + 2]-cycloaddition of two alkynes.</figcaption></figure>

<figure><img src="image_69.png" /><figcaption>**Scheme 35.** Synthesis of C₂-symmetric cyclobutane **175** catalyzed by an alumina supported iron-catalyst.</figcaption></figure>
<figure><img src="image_70.png" /></figure>

<figure><img src="image_71.png" /><figcaption>**Scheme 36.** FeCl₃ catalyzed radical cation-induced [2+2]-cycloaddition of *trans*-anetholes and styrenes.</figcaption></figure>

An improved strategy uses FeCl₃ as a catalyst and diene **176** as redox-mediator to suppress polymerization side reactions and decomposition of the formed products. Using these conditions, the [2+2]-cycloaddition of **177** with **178** afforded various cycobutanes **179** bearing both electron-donating (**180**–**183**) and electron-withdrawing groups (**184**) in good yields (52–93%, Scheme 37).[154]

To modulate the oxidation strength of Fe(III) catalysts, Kang *et al.* tested different phenanthroline-based ligands. With its relatively low oxidation capability, Fe(III)-phenanthryl complex **184** (E₁/₂ = +0.91 V) turned out to be the optimal catalyst to facilitate the [2+2]-cycloaddition, *via* one-electron oxidation, between *trans*-anethole (E₁/₂ = +1.11 V) and styrene in a selective manner (Scheme 38).[155] This catalyst system grants access to a variety of substituted cyclobutanes, including ones featuring an O-allyl (**185**), benzylic chloride (**186**), and OBN functional group (**187**) in moderate to good yields (35–86%,

<figure><img src="image_72.png" /><figcaption>**Scheme 37.** FeCl₃ catalyzed radical cation-induced [2+2]-cycloaddition of *trans*-anetholes and styrenes.</figcaption></figure>

<figure><img src="image_73.png" /><figcaption>**Scheme 38.** Fe(III)-phenanthryl-mediated radical cation-induced [2+2]-cycloaddition of *trans*-anethole and styrenes.</figcaption></figure>

Scheme 38). Oxygen was required to achieve satisfactory yields for the sterically and electronically unfavourable substrates. The authors proposed that the oxygen stabilizes the radical cation **188** in form of dioxetane **189** (Scheme 38, bottom right). Generally, these reactions afford the *trans*-cyclobutene in a stereospecific manner due to C–C rotation of intermediate **188** to form the stable *trans*-intermediate.

## 7. Lewis-Acid Catalyzed [2+2]-Cycloadditions

Approaches employing polarized alkenes in conjunction with a Lewis-acid catalyst have seen broad application in [2+2]-cycloaddition reactions and have proven to be especially successful in the context of enantioselective [2+2]-cycloadditions. The reaction is facilitated by either (i) *σ*-Lewis acids (Fe, Ti, Cu, Ru, Zn, Ag) activating an unsaturated carbonyl towards nucleophilic attack and (ii) cationic *π*-Lewis acids (Au, Pt) coordinating the *π*-system of an alkyne making it susceptible to nucleophilic attack. Advances on this topic, albeit limited to group 11 metals, have been previously reviewed.[19]

### 7.1. [2+2]-Cycloadditions of Polarized Olefins by *σ*-Lewis Acids

Alumina-supported FeCl₃ was reported to facilitate the [2+2]-cycloaddition of (*E*)-enimide **190** and malonate **191** to form aminocyclobutanes **192** in good to excellent yields with good diastereoselectivities (Scheme 39).[156] Enimides bearing alkyl, aliphatic chloro substituents were tolerated (not shown). The methodology also enables the synthesis of succinimide and Boc-protected thymine cyclobutane **193**. Both electron-rich and electron-deficient aromatic enimides underwent [2+2]-cycloaddition to form the corresponding cyclobutanes **194** and **195**. In the case of *p*-methoxybenzene-substituted enimide, the cyclobutane was formed with opposite regioselectivity (**194**, d.r. >20:1). In case of less reactive substituted alkyl-malonates (methyl, cyclohexyl, CH₂CH₂Ph), no stereoselectivity was observed. An exception was observed for the trifluoromethyl-substituted congener, where only *trans*-aminocyclobutane **196** was obtained (76%, d.r. > 20:1). Experiments with stereospecific-

<figure><img src="image_74.png" /><figcaption>**Scheme 39.** Stereoselective Fe-catalyzed synthesis of aminocyclobutanes form (*E*)-enimides and malonates.</figcaption></figure>
<figure><img src="image_75.png" /></figure>

cally deuterated (E)-enimides support a mechanism proceeding
via a zwitterionic intermediate (Scheme 39, top right).

Tang *et al.* reported a stereoselective [2+2]-cycloaddition protocol of N-sulfonyl enamides **197** and with electron deficient dimethyl methylenemalonate **191**, granting access to substituted, tosyl-protected azabicyclo[3.2.0]hexanes and cyclobutanes (e.g. **198**) in good to excellent yields (Scheme 40).[157] Both saturated and unsaturated alkyl and aromatic substituents were tolerated.

Early reports by Reddy *et al.* report highly effective of chiral
Ti-reagents in inducing asymmetry for the [2 + 2]-cycloadditions
between styrenes and 1,4-benzoquinones.[158] Based on this
work, Niihata *et al.* developed the first enantioselective [2 + 2]-
cycloaddition (Scheme 41).[159] In the presence of catalytic
amounts of chiral Ti-TADDOL, generated by mixing TiCl₂(OiPr)₂
and ligand **199**, electron deficient oxazolidones **200**, **202**, **204**
and alkenes or alkynes bearing an alkylthio group (**201**, **203**,
and **205**) could be reacted. The reaction between 3-acryloyl, 3-
crotonoyl and oxyzolidinone and dimethyl dithioacetal **201**
afforded the corresponding cyclobutanes **206** and **207** in good
yields (64% and 96%) and enantioselectivities (80% and 88%
*ee*). The CO₂Me-substituted cyclobutane **208** was also obtained
in excellent yield and essentially enantiomerically pure (96%,
98% *ee*). Cyclic alkenyls **203** underwent [2 + 2]-cycloaddition to
form the corresponding bicyclo[3.2.0]heptane **209**,
bicyclo[4.2.0]octane **210** and bicyclo[6.2.0]decane **211** in good
yields (89–97%) and enantioselectivities (> 98% *ee*). However,
due to the lower reactivity of the cyclic alkenyl, in order to

obtain high yields of 209 and 210, required the use of equimolar amounts of the Ti-reagent. To achieve satisfactory reactivities, alkynyl sulfides relied on unsubstituted or ester-substituted oxazolidinones, which gave the corresponding cyclobutenes 212 and 213 in high yields and enantioselectivities (86/92% yields and > 98% ee).

To facilitate the key step in the first total synthesis of (+)-tricycloclavulone, i.e. the formation of the bicyclic backbone 214, Iguchi et al. developed a chiral catalyst system consisting of CuCl₂, AgSbF₆ and ligand 215 for the enantioselective [2+2]-cycloaddition of 2-methoxycarbonyl-2-cyclopenten-1-one 216 and phenyl thioacetylene 217. The reaction proceeded in good yields (67%) and moderate enantioselectivities (73% ee, Scheme 42),[160,161] and was subsequently applied in the synthesis of (+)-precapnelladiene 218.[162]

Heteroatom-substituted alkynes, especially ynamides, are
very versatile coupling partners in [2+2]-cycloadditions. They
are readily synthesized[163] and facilitate the introduction of
electron-withdrawing groups, therefore tuning down the polar-
ization of the alkyne triple bond. This leads to a good balance
between stability and reactivity. As such, they have seen
widespread use in organic synthesis.[164]

In 1969, Ficini et al. reported the thermal [2 + 2]-cycloaddition of cyclic enones or quinones and ynamides.[165] The thermally driven reaction usually relies on the highly reactive ynamies. The first Cu-catalyzed Ficini reaction was reported in 2011 by Wei et al., extending it to less reactive N-sulfonyl ynamides.[166] In presence of high catalytic amounts CuCl₂ (20 mol%) and AgSbF₆ (60 mol%), N-sulfonyl-substituted ynamides and enones readily underwent [2 + 2]-cycloaddition in moderate to good yields (21–75%, Scheme 43). The approach is

<figure><img src="image_76.png" /><figcaption>**Scheme 40.** Stereoselective Cu-catalyzed protocol to access cyclobutanes and nitrogen containing bicycles.</figcaption></figure>

<figure><img src="image_77.png" /><figcaption>**Scheme 42.** Enantioselective Cu-catalyzed [2 + 2]-cycloaddition and its use in total synthesis.</figcaption></figure>

<figure><img src="image_78.png" /><figcaption>**Scheme 41.** Enantioselective Ti-catalyzed [2 + 2]-cycloaddition of alkylthio-containing olefins.</figcaption></figure>

<figure><img src="image_79.png" /><figcaption>**Scheme 43.** First Cu-catalyzed Ficini reaction between ynamides and (cyclic) enones.</figcaption></figure>
<figure><img src="image_80.png" /></figure>

broadly applicable and tolerates: (a) five- and six-membered cyclic enones (220, and 221 respectively) and acyclic enones (222); (b) both alkyl (222) and phenyl (221) substituted alkynes; (c) different N-sulfonyl groups, such as *p*-Ns (220, 222), Ts (219, 221, 223) or sultam (224); (d) different substituents on the nitrogen atom including alkenes (223) and *tert*-butyldimethylsilyl ethers. In case of the chiral sultam substituents (224), no diastereoselectivity was observed. The formal [2 + 2]-cycloaddition is believed to proceed through a stepwise mechanism via dipolar intermediate 225, formed through nucleophilic attack of the β-carbon of the ynamide on the Lewis-acid activated enone (Scheme 43, top right). Subsequent attack of the enolate on the iminium ion affords the corresponding cyclobutenes.

A protocol for a enantioselective version of the Ficini reaction, catalyzed by Cu(OTf)₂ and ligand 226, was reported by Nakada *et al.* (Scheme 44).[167] The methodology tolerates sterically hindered enones and unreactive ynamides which are readily cyclized at low temperatures in good yields (65–97%). While unsubstituted and methyl-substituted ynamides undergo [2 + 2]-cycloaddition with good enantioselectivities (86/89% ee) to give 227 and 228 respectively, other substituents such phenyl lead to significantly lower enantioselectivities (35% ee for 229). Di-methylated imides and 5-membered imides also underwent cyclization to form the corresponding bicycles (230 and 231).

Mezzetti *et al.* developed an enantioselective version of the Ficini-reaction employing a chiral Ru-salene complex 232.[168,169] (Et₃O)PF₆ activates 232 to form the dicationic active Ru-species. Different functional groups, such as silyl ethers (233) and benzyl ethers (234) are tolerated (Scheme 45). To achieve high yields

and enantioselectivities, a bulky and electron donating R¹ substituent, such as cyclohexyl, are a prerequisite, yielding the target 235 in good yields (97%, > 99.5% ee after crystallization). Smaller ester substituents (236) and cyclohexenones (237) lead to low enantioselectivities (< 60% ee).

Fushimi and coworkers reported the [2 + 2]-cycloaddition of electron-rich, substituted dienes 238 or silyl enol ethers with electron-poor propiolamide 239 in the presence of a chiral 240-Cu(NTf₂)₂ catalyst to give the corresponding cyclobutenes (241–243) in good yields, achieving moderate enantioselectivity (Scheme 46).[170]

Feng *et al.* introduced a methodology for the enantioselective [2 + 2]-cycloaddition of alkynones 244 and cyclic enol silyl ethers 245 for the synthesis of bicyclic cyclobutenes 245–259, catalyzed by a Zn(II) complex bearing a chiral ligand 260 (Scheme 47).[171] In contrast to the previously reported Cu-catalyzed approach (Scheme 43), internal alkynes are also tolerated. Alkynones bearing 2-naphtyl and cyclohexyl substituents readily underwent cyclization to form the corresponding cyclobutenes 245 and 246 with aliphatic substituents resulting in lower ee-values (245, 82% ee in contrast to 246, 97% ee). The methodology also tolerates a broad range of terminal alkynones substituted with electron-withdrawing and electron-donating groups to access cyclobutenes 247–259 in moderate to high yields (65–85%), with high enantioselectivities (94–97% ee). Internal alkynones afforded the cyclobutenes in high yields

<figure><img src="image_81.png" /><figcaption>Scheme 44. Asymmetric Lewis-acid catalyzed [2 + 2]-cycloaddition of Cyclic α-alkylidene β-oxo imides and ynamides.</figcaption></figure>

<figure><img src="image_82.png" /><figcaption>Scheme 45. Enantioselective Ru-catalyzed Ficini-reaction.</figcaption></figure>

<figure><img src="image_83.png" /><figcaption>Scheme 46. Enantioselective Cu-catalyzed [2 + 2]-cycloaddition of terminal alkynes and dienes or enol silyl ethers.</figcaption></figure>

<figure><img src="image_84.png" /><figcaption>Scheme 47. Enantioselective Zn-catalyzed [2 + 2]-cycloaddition of terminal and internal alkynes and enol silyl ethers.</figcaption></figure>
<figure><img src="image_85.png" /></figure>

(252, 74% and 253, 99%), albeit with more moderate ee-values (71–86% ee). Substituted benzocyclic enol silyl ethers gave the cyclobutenes in excellent yields and stereoselectivities (254 and 255). Furthermore, monocyclic enol silyl ethers afforded five-(256, 76%, 83% ee), six-(257, 75%, 86% ee), and eight-membered (258, 26%, 22% ee) rings fused with cyclobutenes. Larger ring-size and acyclic silyl enol ethers gave low yields and showed very modest enantioselectivity.

Chengondi and co-workers recently reported the first [2 + 2]-cycloaddition of unactivated aryl alkynes and enones. Tricyclic butenes 261 were obtained in moderate to excellent yields and excellent stereoselectivities through a Ag-catalyzed [2 + 2]-cycloaddition of cyclohexadienone-substituted 1,7-enynes (262, Scheme 48).[172] While electron-rich alkynes readily undergo [2 + 2]-cycloaddition, the electron-deficient analogues, bearing aryl rings substituted with electron-withdrawing groups, yield the dihydrofurans type 263, through loss of a proton and C–O bond cleavage. (CH₂)OTBS substituents on the quaternary carbon of the cyclohexadienone also gave the [2 + 2]-cycloaddition product whereas Et and n'Pr substituents exclusively formed the corresponding dihydrofuran by-product. Substrates with longer chain length (264) remained unreactive under the reported conditions.

## 7.2. [2 + 2]-Cycloadditions of Alkynes Activated by π-Lewis Acids

The [2 + 2]-cycloadditions involving soft carbophilic Lewis acids rely on Ag(I), Au(I) and Pt(II) species, and usually involve the activation of the alkyne through coordination, followed by the nucleophilic attack of the olefin unit. Metal carbenes or metal vinyl species are often invoked as intermediates. The strategy could be used for both intramolecular and intermolecular cyclization reactions. A more detailed summary is given below.

Highly-substituted azabicyclo[4.2.0]oct-5-enes derivatives (type 265) are accessible in good yields (41–90%) via an intramolecular Au(I)-catalyzed tandem 1,3-migration/[2 + 2]-cycloaddition reaction of 1,7-enyne benzoates 266, reported by Chan *et al.*[173] This methodology tolerates various functional groups such as thiophene, cyclopropane, OTBS, MeSO₂r, or activated alkene moieties (Scheme 49). The reaction is proposed to proceed through activation of the alkyne moiety by the

<figure><img src="image_86.png" /><figcaption>**Scheme 48.** Ag-catalyzed intramolecular [2 + 2]-cycloaddition of cyclohexadienones bearing an alkyne moiety.</figcaption></figure>

<figure><img src="image_87.png" /><figcaption>**Scheme 49.** Intramolecular Au(I)-mediated [2 + 2]-cycloaddition between alkynes and olefins.</figcaption></figure>

Au(I)-catalyst followed by a syn-1,3-migration of the benzyl ester, which results in an allene intermediate. The subsequent [2 + 2]-cycloaddition proceeds with a high selectivity at the distal allene unsaturation, to afford the bicyclic product. Gagosz *et al.* utilized the same approach to isolate a variety of functionalized bicyclo[5.2.0]nonenes via the Au(I)-catalyzed [2 + 2]-cycloaddition of 1,8-enynes. The products were susceptible to follow-up reactions such as Au(I)-catalyzed isomerization and fragmentation of the cyclobutene moiety.[174]

An intermolecular variant of the same reaction was described by Echavarren *et al.*, who reported the Au(I)-catalyzed [2 + 2]-cycloaddition between i) alkenes and ii) terminal alkynes or 1,3-diynes as reaction partners (Scheme 50-a) to give substituted cyclobutenes type 268.[16] Diethynylbenzenes gave the respective bisycyclobutanes in good yields (70–80%). Electron-deficient alkynes lead to varying amounts of side products in the form of 1,3-dienes formed in a metathesis-type reaction. Detailed computational analysis suggested a nucleophilic attack of the olefin on the Au(I)-activated alkyne, yielding a cyclopropyl-containing Au(I)-carbene 269, which further undergoes ring expansion.[175] The use of a non-C₂-chiral JosiPhos digold(I) complex extends this methodology to enantioselective synthesis of cyclobutenes with high enantiose-

<figure><img src="image_88.png" /><figcaption>**Scheme 50.** Intermolecular Au(I)-mediated [2 + 2]-cycloaddition between alkynes, enynes and olefins.</figcaption></figure>
<figure><img src="image_89.png" /></figure>

lectivities (er up to 98:2). Additionally, long-chained 1,n-enynes (n = 10–16) readily undergo [2 + 2]-cycloaddition, granting access to cyclobutene containing 9–15-membered macrocycles. To facilitate this transformation efficiently, the alkyne and alkene moiety must be close and in a stable conformation through incorporation of a phenyl ring in the spacer of the enyne.[176] The utility of this approach was demonstrated in the total synthesis of the natural product Rumphellaone A.[177,178] The strategy could be subsequently employed to get access to 1-vinyl-3-substituted cyclobutenes, through [2 + 2]-cycloaddition of terminal 1,3-enynes with alkenes (Scheme 50-b).[179] Cyclobutene-fused eight-membered carbocycles from the corresponding 1-9-enyne were reported by Sawamura et al. employing triethynylphosphine-based Au(I)-catalysts.[180]

In a related methodology, Echavarren *et al.* explored the reactivity of aryl ynol ethers in the presence of electron-rich alkenes which, under gold catalysis, yield cyclobutene-based enol ethers in varying yields (Scheme 51-a).[181] Due to the high reactivity of the alkyne coupling partner, the method does not require highly activated olefins and tolerates trisubstituted double bonds. DFT calculations support a mechanism where a cyclopropyl-substituted gold(I) carbene is initially formed, followed by ring expansion, similar to the approaches described above (Schemes 49 and 50).

The method is conceptually related and complementary to the silver-catalyzed [2 + 2]-cycloaddition reported by Kozmin *et al.*[182] which uses siloxy alkynes, in reaction with a range of unsaturated carbonyl compounds (Scheme 51-b). Due to the difference in triple bond polarization, the siloxy alkynes act as a C2 electrophiles, where a silver-substituted ketene is proposed as a reaction intermediate. This distinguishes the silver approach from the gold-catalyzed analogue, where the nucleophile is located at the distal carbon atom with respect to the metal center.[181]

A catalytic system for the [2 + 2]-cycloaddition of chlorothynyl arenes and chloroethynyl phenyl sulfide with electronically unactivated alkenes was reported by Zhang *et al.* achieving moderate to excellent yields (Scheme 52).[183] In the case of 1,2-disubstituted alkenes, the [2 + 2]-cycloadditions are generally highly stereospecific. Conceptually similar to other Au(I)-catalyzed reactions,[184] the [2 + 2]-cycloaddition proceeds *via* electrophilic activation of the alkyne by the Lewis-acidic Au(I)

<figure><img src="image_90.png" /><figcaption>**Scheme 52.** Au(I)-catalyzed intermolecular [2 + 2]-cycloaddition of unactivated alkenes.</figcaption></figure>

species to form Au(I)-alkyne complex **270** making it susceptible towards nucleophilic attack by an alkene.

While the gold approaches hitherto utilize isolated cationic complexes as pre-catalysts, an earlier example by Zhang *et al.* makes use of an *in-situ* synthesized (PPh₃)Au(I) cation *via* silver activation (halide abstraction).[185] Using this approach, an intramolecular [2 + 2]-cycloaddition reaction using propargyl alkynes and indoles as coupling partners yielded highly functionalized 2,3-indoline-fused cyclobutene derivatives (Scheme 53). Mechanistically, the gold(I) activated propargyl alkyne undergoes nucleophilic attack by the adjacent acetate group, triggering a 3,3-rearrangement of the indole-3-acetoxy group. The thus formed allenylic ester **271** undergoes further activation by the cationic catalyst, and subsequent cyclization yields the product **272**. The key allenylic ester intermediate **271** could be observed via ¹H NMR spectroscopy and could be independently synthesized by treating the starting material **273** with AuCl₃. This intermediate undergoes conversion to the cyclobutene **272** under standard catalytic conditions (74% yield), supporting the proposed mechanism.

Apart from Au(I) and Ag(I)-based methodologies, an early report by Fürstner *et al.* used Pt(II)-carbophilic Lewis acids for

<figure><img src="image_91.png" /><figcaption>**Scheme 53.** Au-mediated intramolecular [2 + 2]-cycloaddition of indole-containing propargyl carboxylates to yield 2,3-indoline-fused cyclobutanes.</figcaption></figure>

<figure><img src="image_92.png" /><figcaption>**Scheme 51.** Au- and Ag-catalyzed synthesis of cyclobutyl enol ethers *via* [2 + 2]-cycloaddition of ynol ethers and alkenes.</figcaption></figure>
<figure><img src="image_93.png" /></figure>

<figure><img src="image_94.png" /><figcaption>**Scheme 54.** Cycloaddition of enynes in the presence of Pt(II) catalysts to yield cyclobutene-containing polycyclic derivatives.</figcaption></figure>

the intramolecular cycloaddition of electron-deficient alkynes with cyclic and acyclic olefins (Scheme 54).[186,187] This methodology gave rise to cyclobutene-derived bicyclic or polycyclic systems. Mechanistically, the authors suggested the intermediacy of a non-classical cation, whose formation is triggered by the activation of the alkyne in the presence of the platinum catalyst. This cation rearranges to the zwitterionic intermediate 275, which undergoes deprotonation, formally eliminating a platinum hydride and the observed reaction product (e.g. **276a**, **277a**). The selectivity of the reaction is dependent on the substitution pattern of the alkyne, where selectivities towards the formation of the cyclobutene derivatives are observed when substituents capable of stabilizing the carbocation intermediate are chosen. The reaction rates show significant enhancements in the presence of CO gas, while only poor conversions were observed under argon atmosphere. The role of CO remains to be explained, but it appears to suppress a competing reaction pathway, consisting in a platinum-triggered a cyclorearrangement, to give 1-vinylcycloalkenes, previously reported by Murai *et al.*[188] Subsequently, Tenaglia *et al.* reported the PtCl₂-catalyzed synthesis of aza(oxa)bicyclo[3.2.0]heptenes and showed that employing substrates bearing propargylic alkyl substituents in conjunction with the use of an amide solvent removes the necessity of a CO atmosphere.[189]

## 8. Summary and Outlook

The field of thermally-driven [2 + 2] cycloadditions has made remarkable progress in overcoming the orbital symmetry constraints that limit direct, concerted approaches. Strategies such as cyclometallation, Lewis acid-induced charge polarization, and single-electron transfer from metal centers have expanded the scope and versatility of these transformations. Establishment of structure-activity relationships have contributed to the development of highly active catalysts which has significantly broadened both the scope of applications and the range of metals employed.

Initially reliant on strained or electron-deficient substrates (e.g. norbornadienes) or electron-deficient alkynes, recent advancements now enable the efficient cycloaddition of unactivated substrates, such as simple ethylenes, through the use of catalysts based on earth-abundant metals, including Ti, Fe, Co, and Ni. This shift from noble to abundant metals highlights a growing emphasis on sustainability without compromising catalytic performance. In fact, 3d metals have exhibited reactivity patterns orthogonal to those of their noble counterparts, occasionally achieving superior catalytic activity. However, their use typically demands exceptionally pure substrates and strict exclusion of oxygen and moisture, presenting an additional challenge for their broader application.

All in all, the progress achieved in recent years underscores the importance and urgency of developing non-photochemical protocols for constructing cyclobutane and cyclobutene-containing motifs. These protocols enable the incorporation of functional groups that are otherwise incompatible with photochemical methods, thereby enhancing functional group diversity – a critical factor for their application as drug components. Additionally, eliminating the reliance on light sources addresses the scalability challenges associated with traditional UV-based procedures.

Despite significant advances, several challenges remain, particularly in achieving enantioselective transformations. While Lewis acid catalysis has shown notable success, replicating similar levels of enantioselectivity via cyclometallation/reductive elimination mechanisms remains an open challenge and a promising area for further exploration. Additionally, developing protocols that accommodate unactivated internal and bulkier olefins continues to pose difficulties.

In the context of intramolecular ring-closing [2 + 2]-cycloadditions, cyclobutane motifs fused to five-membered rings are easily accessible from the corresponding olefins since they are thermodynamically favored, while methods yielding six- or seven-membered rings are achievable with only a very limited number of catalytic frameworks. Direct synthetic access to cyclobutanes fused with ring sizes larger than seven, from the corresponding olefins remain inaccessible with current methodologies. Addressing these challenges will require advancements in ligand design and deeper mechanistic insights to broaden the scope and efficiency of these transformations.

## Acknowledgements

Generous financial support from the Fonds der Chemischen Industrie (FCI) and the Deutsche Forschungsgemeinschaft (RO 5979/2-1) is gratefully acknowledged. We thank Prof. Lutz H. Gade for generous support and continued interest in our work and Levi Ziegenhagen for assistance with the TOC graphic. Open Access funding enabled and organized by Projekt DEAL.
<figure><img src="image_95.png" /></figure>

Conflict of Interests

The authors declare no conflict of interest.

Data Availability Statement

Data sharing is not applicable to this article as no new data
were created or analyzed in this study.

Keywords: cycloaddition • transition metals • catalysis • mechanisms

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Manuscript received: December 16, 2024

Revised manuscript received: February 19, 2025

Accepted manuscript online: February 20, 2025

Version of record online: March 15, 2025