# Formation of Substituted Benzocyclobutenes Starting from Donor-Acceptor Cyclopropanes

Bohdan Biletskyi, Maxime Dousset, Pierre Colonna, Virginie Héran, Yannick

Carissan, Laurent Commeiras, Gaëlle Chouraqui

► To cite this version:

Bohdan Biletskyi, Maxime Dousset, Pierre Colonna, Virginie Héran, Yannick Carissan, et al. Formation of Substituted Benzocyclobutenes Starting from Donor-Acceptor Cyclopropanes. Journal of Organic Chemistry, 2025, 90 (11), pp.4115-4120. 10.1021/acs.joc.4c02926. hal-05206398

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# Formation of Substituted Benzocyclobutenes Starting from Donor-Acceptor Cyclopropanes

Bohdan Biletskyi, Maxime Dousset, Pierre Colonna, Virginie Héran, Yannick Carissan, Laurent Commeiras,* and Gaëlle Chouraqui*

**ABSTRACT:** We describe an operationally simple, good-yielding, two-step cascade process to convert biscyclopropanes 1 into high-value benzocyclobutene building blocks 3. This study highlights the novel reactivity of our "in-house" donor-acceptor cyclopropane, achieving complete diastereoselectivity and regioselectivity transfer.

<figure><img src="image_2.png" /></figure>

Donor-acceptor cyclopropanes (DACs) are remarkable chemical species that have been extensively used as valuable 1,3-dipole synthetic building blocks.¹,² The opposing electronic properties of the vicinal substituents, combined with the ring strain of the cyclopropane (~27.5 kcal·mol⁻¹), direct and facilitate the bond scission. This push-pull effect has found wide applications in synthetically useful organic reactions.³ Recently, authors have shown interest in exploring different donor patterns, stepping away from the classical O, N, or phenyl donor substituents.⁴ Interestingly, Tomilov, Novikov,⁵ and Werz⁶ showed that the cyclopropyl group can act as an excellent donor (Scheme 1, eq 1). For instance, Werz and co-workers illustrated that various (3+n) cycloaddition reactions could be achieved, resulting in valuable small-ring

substituted cyclic systems. Inspired by this work, our group also contributed to the field.⁷ In a recent communication, we reported that eight-membered carbocyclic ring compounds 2 could be obtained from an original biscyclopropane DACs 1a, in 83% yield, under thermal conditions, after 72 h in boiling xylene (Scheme 1, eq 2).⁷b The three-atom donor component was this time embedded in the challenging medium-size ring 2. We hypothesized that we could further enhance the electron-donating ability of the cyclopropanol and thereby accelerate the reaction by using fluoride anions in the reaction mixture. The reaction was carried out using 1 equiv of tetra-butylammonium fluoride in boiling THF for 16 h. However, the expected eight-membered ring 2 was not observed; instead, benzocyclobutene 3a was isolated in good yield (61%) (Scheme 1, eq 3). This preliminary serendipitous result showed that deprotection of the silyl ether initiated by a fluoride anion triggered a ring-expansion/ring-opening/ring-closure domino sequence.

The mechanistic scenario presented in Scheme 2 could plausibly describe the reaction pathway. The DAC precursor 1a could first undergo deprotection of the tertiary alcohol in the presence of the fluoride anion. The corresponding alkoxide 4a could then perform a hetero Michael addition onto the vinyl ester, followed by a retro-Michael reaction, resulting in the cyclopropane-cyclopropanol ring expansion to cyclo-

<figure><img src="image_3.png" /><figcaption>**Scheme 1. Cyclopropyle Group as a Donor in DACs**</figcaption></figure>
### Scheme 2. Mechanism for the Formation of 3a

<figure><img src="image_4.png" /></figure>

butanone 6a. In fact, we drew a parallel with the reactivity of 1-silyloxy-1-vinylcyclopropanes popularized by Trost and subsequently exploited by others.⁸ We hypothesized that a similar ring expansion could be observed if the double bond was replaced with a cyclopropane. Accordingly, the ring tension imparted by this additional small ring should be sufficient to trigger the reaction. Alternatively, alkoxide 4a could directly lead to the formation of cyclobutanone 6a. Thereafter, we suggest an intramolecular aldolization step leading to bicyclic system 7a. Finally, the water present in TBAF (1 M solution in THF) generates TBAOH, which could promote E₁cB water elimination to form a cyclohexadiene. This could be followed by a spontaneous aromatization in the presence of dioxygen⁹ (due to the nondegassed solvents), leading to the formation of the isolated compound 3a.

Benzocyclobutenes are crucial motifs in organic synthesis and serve as key structural elements.¹⁰ Upon thermal activation, they can isomerize to the corresponding ortho-quinodimethanes.¹¹ The latter serve as building blocks in the synthesis of natural products and drugs¹² and find application in polymer chemistry and material science.¹³ Several synthetic methods have been developed for the formation of benzocyclobutenes.¹⁰,¹⁴,¹⁵ While each method has its advantages and disadvantages, few are both general and chemo-selective, limiting their applications and utility as key synthetic intermediates. Therefore, the development of alternative and complementary methods to access these compounds is particularly appealing. Herein, we describe an unprecedented protocol for the synthesis of functionalized benzocyclobutenes starting from a donor-acceptor cyclopropane.

Initially, the proposed mechanism (Scheme 2) was confirmed through an experimental step-by-step strategy. This approach involved isolating and characterizing hypothesized intermediates 5a, 6a, and 7a. The successful transformation of these compounds into the final product 3a subsequently supported the overall suggested mechanistic path (see the Supporting Information for more details).

Having established the feasibility of this intramolecular domino reaction, we sought to further examine its substrate scope. Changes were made by varying the substitution on either the donor part (in blue) or the acceptor component (in pink) (Scheme 3). The different bis-vinylcyclopropanes, prepared according to previous reported literature,¹⁷ present

### Scheme 3. Examining the Scope: Unexpected Limitations

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

four stereocenters and usually only two main diastereomers, 1 and 1', were observed (Scheme 3). However, the domino reaction conditions (an equivalent of TBAF in boiling THF) on these valuable substituted donor-acceptor cyclopropanes (when R¹ ≠ H) failed to deliver expected products 3. It led to either the decomposition of the starting material 1 and 1' (when R¹ = Ph) or the isolation of the corresponding THF derivative S (when R¹ = iPr). Screening of the different reaction parameters could not lead to any significant improvement. Therefore, a revised strategy was necessary and relied on a two-step path.

In the presence of 0.5 equiv of a Lewis acid, such as magnesium(II) iodide, the model DAC substrate 1a (R¹ = H) provided a (6,4) bicyclic scaffold 8a quantitatively and diastereoselectively. The reaction proceeded very fast, taking only 10 min in 1,2-dichloroethane at room temperature (Scheme 4). From a mechanistic standpoint, we hypothesized

### Scheme 4. An Alternative Two-Step Strategy

<figure><img src="image_6.png" /></figure>

that the Lewis acid could activate the carbonyl group of the α,β-unsaturated ester and consequently trigger the cleavage of the donor-acceptor cyclopropane bond, leading thereafter, and as described previously, to the ring expansion of the adjacent protected cyclopropanol. This was evidenced by the successful trapping of the transient cyclobutanone 6a' simply by working in a protic medium (Scheme 4). Gratifyingly, the mild Lewis acid conditions allowed us to perform the ring-expansion/ring-opening/ring-closure domino sequence in a single step; however, benzocyclobutene had yet to be reached. A subsequent step was necessary and utilized conditions reported by Levacher.¹⁶ The organocatalyzed interconversion of the silyl ether 8a to the corresponding tosylate using DBU (3 equiv) and p-toluenesulfonyl fluoride (1.2 equiv) was performed in acetonitrile. The reaction, however, was run at 70 °C in a microwave reactor instead of the classical room temperature procedure to induce a subsequent elimination of the OTs group/aromatization sequence. Benzocyclobutene 3a was obtained in a good yield of 59%.

We then proceeded to examine the substrate scope of this strategy. The two-step approach proved to be compatible with alkyl groups on the donor part of the starting biscyclopropanes (Table 1, entries 1–6). The corresponding benzocyclobutenes were obtained in good yields (ranging from 52 to 77% over 2
<figure><img src="image_7.png" /><figcaption>**Table 1. Substrate Scope of the Reaction**</figcaption></figure>

<table><thead><tr><th>Entry</th><th>BiscyclopropaneR, 1:1<sup>a</sup> dr<sup>a</sup></th><th>t step<sup>b</sup></th><th>Yield of 3 + 3' (over 2 steps)</th><th>rr 3 + 3'</th></tr></thead><tbody><tr><td>1</td><td>H<sub>3</sub> 1a<br>E = E' = CO<sub>3</sub>Et</td><td>10 min</td><td>77% 3a (61% 3a)<sup>d</sup></td><td>—</td></tr><tr><td>2</td><td>Me, 1b:1b', 50:50<br>E = E' = CO<sub>3</sub>Et</td><td>60 min</td><td>60% 3b+3b'</td><td>50:50</td></tr><tr><td>3</td><td>δPr, 1c:1c', &gt;95:5<br>E = E' = CO<sub>3</sub>Et</td><td>10 min</td><td>74% 3c+3c'</td><td>88:12</td></tr><tr><td>4</td><td>ω-Hex, 1d:1d', 66:33<br>E = E' = CO<sub>3</sub>Et</td><td>30 min</td><td>54% 3d+3d'</td><td>66:33</td></tr><tr><td>5</td><td>Cy, 1e:1e', 94:6<br>E = E' = CO<sub>3</sub>Et</td><td>15 min</td><td>52% 3e+3e'</td><td>85:15</td></tr><tr><td>6</td><td>CH<sub>3</sub>(OBn), 1f:1f', 89:11<br>E = E' = CO<sub>3</sub>Et</td><td>15 min</td><td>66% 3f+3f'</td><td>92:8</td></tr><tr><td>7</td><td>Ph, 1g:1g', &gt;95:5<sup>b</sup><br>E = E' = CO<sub>3</sub>Et</td><td>120 min</td><td>53% 3g<sup>c</sup></td><td>5: &gt;95</td></tr><tr><td>8</td><td>pMeOPh, 1h:1h', &gt;95:5<sup>b</sup><br>E = E' = CO<sub>3</sub>Et</td><td>60 min</td><td>20% 3h<sup>c</sup></td><td>5: &gt;95</td></tr><tr><td>9</td><td>pFPh, 1i:1i', &gt;95:5<sup>b</sup><br>E = E' = CO<sub>3</sub>Et</td><td>90 min</td><td>40% 3i<sup>c</sup></td><td>5: &gt;95</td></tr><tr><td>10</td><td>δTol, 1j:1j', &gt;95:5<sup>b</sup><br>E = E' = CO<sub>3</sub>Et</td><td>120 min</td><td>37% 3j<sup>c</sup></td><td>5: &gt;95</td></tr><tr><td>11</td><td>H<sub>3</sub> 1k<br>E = CO<sub>3</sub>Et, E' = Ts<sub>3</sub><br>83:17</td><td>120 min</td><td>36% 3k (40% 3k)<sup>d</sup></td><td>—</td></tr><tr><td>12</td><td>Me, 1b<br>E = E' = CO<sub>3</sub>Et</td><td>60 min</td><td>77% 3b</td><td>&gt;95:5</td></tr><tr><td>13</td><td>Me, 1b'<br>E = E' = CO<sub>3</sub>Et</td><td>60 min</td><td>56% 3b'</td><td>&gt;95:5</td></tr></tbody></table>

steps) and as a mixture of regioisomers (50:50 to 92:8 r.r.), a ratio comparable to the initial diastereomeric one of 1 and 1'. The phenyl-substituted DAC 1g exhibited lower stability under the reaction conditions and necessitated a modified procedure to develop a reliable and robust method. Consequently, the amount of Mgl₂ was increased to an equivalent for the first step, and the elimination step was run at room temperature in the presence of an equivalent of TsF and two equivalents of DBU. Benzocyclobutene 3g' was obtained as a single regioisomer¹⁷ in 53% yield over two steps (namely 73% per step) (entry 7). The same procedure was successfully utilized for other sensitive aryle derivatives (entries 8–10). Subsequently, attention was directed toward the accepting part of the molecule. The reaction turned out to be compatible with E' = Ts (entry 11).

At that stage, we began to wonder if there was a correlation between the regioselectivity observed in 3 and 3' (entries 2–6)

and the nature of the starting diastereomer 1 or 1' involved. To test this hypothesis, the reaction was repeated on pure separated diastereomer 1b and 1b' (entries 12 and 13, respectively). As suspected, the reaction displayed complete regioselectivity. In the presence of magnesium iodide in dichloroethane at 20 °C, each biscyclopropane vinyl diastereomer 1b and 1b' was transformed into the corresponding regioisomers 8b and 8b', respectively, each as a single diastereomer. Subsequently, the tosylation/elimination/aromatization step furnished the benzocyclobutenes 3b and 3b' as separate single regioisomers. These results indicated that the C6–C7 bond is broken during the cycloisomerization for diastereomer 1b, leading to regioselectivity where the methyl group is in the α-position of the OTBS substituent. This ring expansion could transiently lead to the formation of cyclobutanone A (Scheme 5a). The relative cis configuration

**Scheme 5. Diastereoselectivity/Regioselectivity Total Transfer**

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

between the Me and H of this intermediate would thus be retained after the intramolecular cyclization step leading to the formation of the bicyclic compound 8b. In the case of 1b', the cleaved bond is the C6–C8 one, delivering the β-regioisomer 8b' via transient species B (Scheme 5b). A brief DFT investigation confirmed the specificity of the reaction, as detailed in the Supporting Information.

Interestingly, the aryl-substituted diastereomers 1g–j (entries 7–10) displayed complementary regioselectivity. In each case, as confirmed by diffraction X-ray analysis,⁷,¹⁸ only the regioisomer 3'—resulting from the selective cleavage of the C6–C8 bond—was isolated. This selectivity between alkyl and aryl functionalities in cyclopropyl ethers has been reported in two previous instances,⁷,¹⁹ further supporting our observations. Moreover, similar patterns of selectivity are observed in other cyclization reactions, such as the acid-mediated carbonyl-olefin [2 + 2] cycloaddition, indicating that this phenomenon is not limited to cyclopropyl ethers alone.²⁰ In ring expansion reactions, the preference for which bond migrates often depends on both steric and electronic factors as well as the specific reaction mechanism. In the case of alkyl substituents, it is more likely that a concerted mechanism is operative (see Supporting Information). Therefore, migration of the bond that minimizes steric strain in the transition state may be favored. However, when the substituent is changed to an aryl group, the benzyl carbocation can be significantly stabilized, potentially favoring a stepwise mechanism instead.¹⁹ Thus, the reactivity of the DAC scaffolds can be fine-tuned by altering the electronic properties of the substituents.

<footnote><sup>a</sup>dr ratio determined by ¹H NMR spectroscopy. <sup>b</sup>Purified by recrystallization. <sup>c</sup>Modified conditions: (a) Mgl₂ (1 equiv), (b) TsF (1 equiv), DBU (2 equiv), room temperature. <sup>d</sup>TBAF conditions.</footnote>
In conclusion, the most significant aspect of this approach is the ring-expansion/ring-opening/ring-closure domino sequence performed in a single step. This strategy yields the corresponding bicyclo[4.2.0]oct-3-ene scaffolds, leading to the formation of valuable functionalized benzocyclobutene systems from readily available precursors, and demonstrates compatibility with a range of functionalities. Notably, this mechanism facilitates a total dia- to regioselectivity transfer, comprising two main-steps and six elementary transformations, thereby highlighting the significant potential of this approach.

### Accession Codes

Deposition Numbers 2338433, 2338337, 2338339, and 2343131 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting the Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033

## ■ AUTHOR INFORMATION

### Corresponding Authors

Laurent Commeiras — Aix Marseille Univ, CNRS, Centrale Med, ISM2, 13397 Marseille, France; orcid.org/0000-0003-4331-6198; Email: laurent.commeiras@univ-amu.fr

Gaëlle Chouraqui — Aix Marseille Univ, CNRS, Centrale Med, ISM2, 13397 Marseille, France; orcid.org/0000-0003-4719-137X; Email: gaëlle.chouraqui@univ-amu.fr

### Authors

Bohdan Biletskyi — Aix Marseille Univ, CNRS, Centrale Med, ISM2, 13397 Marseille, France

Maxime Dousset — Aix Marseille Univ, CNRS, Centrale Med, ISM2, 13397 Marseille, France

Pierre Colonna — Aix Marseille Univ, CNRS, Centrale Med, ISM2, 13397 Marseille, France

Virginia Héran — Aix Marseille Univ, CNRS, Centrale Med, ISM2, 13397 Marseille, France

Yannick Carissan — Aix Marseille Univ, CNRS, Centrale Med, ISM2, 13397 Marseille, France; orcid.org/0000-0002-9876-0272

### Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

### Notes

The authors declare no competing financial interest.

## ■ ACKNOWLEDGMENTS

We gratefully acknowledge the Agence Nationale de la Recherche (project ANR-18-CE07-0005/Benz) for its financial support, including Ph.D. and Postdoctoral grants for P.C. and B.B., respectively. M.D. thanks the French Ministère de l'Enseignement Supérieur et de la Recherche (MESR) for a Ph.D. fellowship. All authors are grateful to Dr. Michel Giorgi from Spectropole for conducting X-ray diffraction structural analysis and to Dr. Nicolas Vanthuyne from Chiropole for HPLC separations. We also acknowledge institutional financial support from Aix-Marseille Université (AMU), the Centre National de la Recherche Scientifique (CNRS), and Centrale Méditerranée. G.C. expresses gratitude to Drs. Jean-Luc Parrain and Yoann Coquerel (Aix Marseille Univ, CNRS, ISM2, Marseille, France) for fruitful and constructive discussions.

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(10) For reviews, see: (a) Kotha, S.; Lahiri, K.; Tangella, Y. Recent Advances in Benzocyclobutene Chemistry. Asian J. Org. Chem. 2021, 10, 3166–3185. (b) Mehta, G.; Kotha, S. Recent Chemistry of Benzocyclobutenes. Tetrahedron 2001, 57, 625–659. (c) Sadana, A. K.; Saini, R. K.; Billups, W. E. Cyclobutarenes and Related Compounds. Chem. Rev. 2003, 103, 1539–1602.

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(13) (a) Kirchhoff, R. A.; Bruza, K. J. Benzocyclobutenes in Polymer Synthesis. Prog. Polym. Sci. 1993, 18, 85–85. (b) Farona, M. F. Benzocyclobutenes in Polymer Chemistry. Prog. Polym. Sci. 1996, 21, 505–555. (c) Cheng, Y.; Tian, S.; Shi, Y.; Chen, W.; Li, Z.; Zhu, T.; Zhang, Z. Benzocyclobutene Organosiloxane Resins Prepared by Alcoholysis of BCB Functionalized Chlorosilane for Highly Cross-linked Low-k Thermosets. Eur. Polym. J. 2017, 95, 440–447. (d) Hayes, C. O.; Chen, P.-H.; Thedford, R. P.; Ellison, C. J.; Dong, G.; Willson, C. G. Effect of Ring Functionalization on the Reaction Temperature of Benzocyclobutene Thermoset Polymers. Macromolecules 2016, 49, 3706–3715. (e) Huang, Y.; Zhang, S.; Hu, H.; Wei, X.; Yu, H.; Yang, J. Photoactive Polymers with Benzocyclobutene/Silacyclobutane Dual Crosslinked Structure and Low Dielectric Constant. J. Polym. Sci. Part A 2017, 55, 1920–1928. (f) Yang, L.; Cao, K.; Huang, Y.; Chang, G.; Zhu, F.; Yang, J. Synthesis and Properties of Cross-Linkable Polysiloxane via Incorporating Benzocyclobutene. HighPerform. Polym. 2014, 26, 463–469. (g) Tian, S.; Sun, J.; Jin, K.; Wang, J.; He, F.; Zheng, S.; Fang, Q. Postpolymerization of a Fluorinated and Reactive Poly(aryl ether): An Efficient Way To Balance the Solubility and Solvent
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(14) For seminal reports, see: Finkelstein, H. Darstellung Organischer Jodide aus den Entsprechenden Bromiden und Chloriden. Chem. Ber. 1910, 43, 1528–1532.

(15) For selected examples, see: (a) Chaumontet, M.; Piccardi, R.; Audic, N.; Hitce, J.; Peglion, J.-L.; Clot, E.; Baudoin, O. Synthesis of Benzocyclobutenes by Palladium-Catalyzed C–H Activation of Methyl Groups: Method and Mechanistic Study. J. Am. Chem. Soc. 2008, 130, 15157–15166. (b) Wu, Z.; Ma, D.; Zhou, B.; Ji, X.; Ma, X.; Wang, X.; Zhang, Y. Palladium-Catalyzed Alkylation with Alkyl Halides by C(sp $^{3}$)–H Activation. Angew. Chem., Int. Ed. 2017, 56, 12288–12291. (c) Bezenšek, J.; Groselj, U.; Počkaj, M.; Svete, J.; Stanovnik, B. Formation of Benzocyclobutenes from Substituted Oxocycloocta-2,8-diene-1,2-dicarboxylates. Tetrahedron Lett. 2015, 56, 5705–5708. (d) Chen, G.-A.; Fang, A.; Wei, Y.; Tang, X.-Y.; Shi, M. Gold(I)-Catalyzed Dehydrogenative Cycloisomerization of 1,5-Enynes. Chem. Commun. 2016, 52, 10799–10802.

(16) Gembus, V.; Marsais, F.; Levacher, V. An Efficient Organo-catalyzed Interconversion of Silyl Ethers to Tosylates Using DBU and p-Toluenesulfonyl Fluoride. Synlett 2008, 2008, 1463–1466.

(17) Fortunately, compound 3g$^{′}$ proved to be crystalline, and the regioselectivity was unambiguously secured through X-ray crystallographic analysis. The crystal structure has been deposited at the Cambridge Crystallographic Data Centre (deposition number CCDC-2338339)

(18) The crystal structure of 3j$^{′}$ has been deposited at the Cambridge Crystallographic Data Centre (deposition number CCDC-2343131)

(19) Cheng, X.; Yin, Q.; Jiang, Y.-X.; Jiang, L.-F.; Li, S.-Y.; Cheng, Y.-F.; Sun, X.-C.; Peng, L.; Zhong, C.; Deng, Q.-H. Simple and Versatile Nitrooxylation: Noncyclic Hypervalent Iodine Nitrooxyating Reagent. Angew. Chem., Int. Ed. 2023, 62, No. e202302521.

(20) Li, Y.-Y.; Zhang, S.-A.; Hong, X. An Asynchronous Concerted Mechanism and Its Origin in Lewis Acid-Mediated Carbonyl-Olefin [2 + 2] Cycloaddition. Chem.—Asian J. 2023, 18, No. e202300375.