# Orthogonal Syntheses of 3.2.0 Bicycles from Enallenes
## Promoted by Visible Light

Andrea Serafino, Davide Balestri, Luciano Marchiò, Max Malacria, Etienne Derat, Giovanni Maestri

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► To cite this version:

Andrea Serafino, Davide Balestri, Luciano Marchiò, Max Malacria, Etienne Derat, et al.. Orthogonal Syntheses of 3.2.0 Bicycles from Enallenes Promoted by Visible Light. Organic Letters, 2020, 22 (16), pp.6354-6359. 10.1021/acs.orglett.0c02193. hal-04049793

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# Orthogonal Syntheses of 3.2.0 Bicycles from Enallenes Promoted by Visible Light

Andrea Serafino, Davide Balestri, Luciano Marchiò, Max Malacria, Etienne Derat, and Giovanni Maestri*

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Cite This: *Org. Lett.* 2020, 22, 6354–6359

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Supporting Information

**ABSTRACT:** Enallenes can be readily converted into two families of 3.2.0 (hetero)bicycles with high diastereoselectivities through the combination of visible light with a suitable Ir(III) complex (1 mol %). Two complementary pathways, namely, a photocycloaddition versus a radical chain, can then take place. Both manifolds grant complete regiocontrol of the allene difunctionalization. This is accompanied by an original 1,3-group shift using sulfonyl allenamides that deliver a congested tetrasubstituted headbridging carbon in the corresponding product.

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The 3.2.0 bicyclic unit is found in a myriad of natural products and functional bioactive molecules.¹ Several of these examples feature an alkene motif that suggests sealing the four-membered ring via an intramolecular [2 + 2] cycloaddition from an enallene.² However, the allene functionalization presents regiochemical challenges (*Scheme 1*). This issue is shown in the synthesis of Bielschowskysin, in which a mixture of isomers was observed in the key annulation promoted by UV-C light.³

<figure><img src="image_9.png" /><figcaption>**Scheme 1.** 3.2.0 Unit in Functional Molecules and Regiochemical Issues in [2 + 2] Photocycloaddition of Enallenes</figcaption></figure>

Complete regiochemical control has been achieved in a few cases (*Scheme 2*). The thermal activation of 1,7-enallenes leads to the corresponding 4.2.0 bicycles with an endocyclic C—C double bond.⁴ However, this approach requires heating to 150 °C. Cationic gold(I) complexes can smoothly activate analogous substrates at room temperature, leading to 3.2.0 products instead. However, a selective reaction requires that

<figure><img src="image_10.png" /><figcaption>**Scheme 2.** Regiocontrol in [2 + 2] Cycloadditions of Enallenes</figcaption></figure>

Received: July 2, 2020

Published: August 5, 2020

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the gold catalyst could discriminate between the two cumulated double bonds, limiting the method to trisubstituted allenes.⁵

We report here the first general visible-light-promoted cyclization method using enallenes. This approach uses an Ir(III) photoactive complex to activate the alkene arm,⁶ pivoting on the seminal work of Yoon on the activation of styryl fragments, regardless of their electronic demands,²e via energy transfer (eT)⁶a,b to trigger intramolecular [2 + 2] cycloadditions with a tethered alkene partner. This strategy is complementary to thermal and organometallic strategies for the cyclization of enallenes. The present process allows us to control the functionalization of *either* the proximal or the distal position of the allenyl fragment.

The reaction of 1,7-enallenes **1** delivers 3.2.0 bicycles **2**, which have three contiguous stereocenters, with high region- and diastereocontrol. A different tether between the two unsaturated partners reverts the outcome under otherwise identical conditions. Indeed, the use of 1,6-enallenes **3** leads to products **4**. Furthermore, a formal 1,3-sigmatropic rearrangement of sulfonyl groups occurs,⁷ creating a sterically congested quaternary carbon at the headbridge position and an imine function. This synthetically challenging architecture likely forms through the propagation of a radical chain, in striking contrast with the catalytic photocycloaddition that gives product **2**.

We turned our attention to the reactivity of 1,7-enallene **1a** as part of an ongoing interest in the cyclization sequences of polyunsaturated substrates that allow complete atom economy.⁸ We found that **1a** could smoothly deliver **2a** in 82% isolated yield in the presence of 1 mol % of Ir(III) complex **A** (*Figure 1*) upon a preliminary screening of the reaction conditions. Reactions were carried out on 0.2 mmol scale under N₂ in degassed dimethylformamide (DMF). The mixtures were placed in nuclear magnetic resonance (NMR) tubes, kept at 25 °C without stirring, and irradiated for 16 h with a light-emitting diode (LED) strip.⁹ The structure of **2a** was confirmed by X-ray analysis, which confirmed the relative configuration of the three stereocenters initially assigned by correlation NMR experiments.

Encouraged by this result, we prepared a library of 1,7-enallenes through homologation of the corresponding 1,6-enynes.¹⁰ The styryl arm could be decorated by electron-withdrawing groups, including halides and cyano and trifluoromethyl groups, and the corresponding products were retrieved in moderate to good yields (2b–e, 53–67%). Similarly, the presence of donating substituents was well tolerated (2f,g, 63 and 80%, respectively), although the diastereocontrol was lower using reagent **1g** (dr = 6:1). Heteroaromatics could be employed, as witnessed by **2h**, which had a 3-pyridyl group (59%). The presence of an ethereal tether led to **2j** (49%, dr = 9:1). Complete control of the functionalization of the allene proximal double bond was observed using a trisubstituted allene (2k, 66%). A disubstituted one followed suit (2i, 71%), although the product was retrieved as mixture of E/Z isomers (5:1). The substrate **1l**, which had a styryl arm and a phenylallene arm, afforded two products. Together with **2l** (39%, 1:1 E/Z mixture), we isolated 2'-l in 35% yield and clarified its structure by X-ray analysis. It had a 4.2.0 bicyclic unit with three contiguous stereocenters, and its two phenyl rings were anti with respect to each other. The structure of 2'-l showed

that difunctionalization of the distal double bond of the allene might have been possible under the present conditions.

We thus thought to elicit a distal-selective variant of the reaction by preparing 1,6-enallenes, reasoning that the formation of a 3.2.0 product 4' would have been favored over that of the corresponding 2.2.0 product (4'', Figure 2). Substrates were synthesized by isomerization of the corresponding 1,6-enynes. Gratifyingly, the reaction of **3a** indeed gave a 3.2.0 bicycle. However, crystallization and subsequent X-ray analysis revealed that its structure was different from the expected one, namely, 4'. Surprisingly, sulfonamide activation and formal 1,3-sigmatropic rearrangement of the sulfonyl group took place,⁷ eventually delivering bicyclic imine **4a** (59%) as a single diastereoisomer. To the best of our knowledge, this reactivity has not been previously reported in sequences promoted by visible light.¹¹ We therefore tested its generality.

The method could be extended to different styryl partners, delivering the corresponding products **4b–e** in moderate to good yields. Electron-rich aromatics, both ortho- and para-

<figure><img src="image_12.png" /><figcaption>**Figure 1.** Synthesis of vinylidencyclobutanes **2**.</figcaption></figure>
<figure><img src="image_13.png" /><figcaption>Figure 2. Synthesis of 3.2.0 heterobicycles 4.</figcaption></figure>

substituted (4b,c, 53–58%), performed better than those with withdrawing groups (4d,e, 31–38%). The tosyl group could be replaced by a mesyl group (4f,g, 49–55%). Similarly, various arylsulfonyl groups were employed (4h–l), including bulky mesitylene and naphthalene units. The variation was well tolerated by the reaction (46–68%), with the partial exception of the nosyl derivative, which gave the corresponding product in 27% yield. A longer tether enabled us to access a tetrahydropyridine unit, albeit with a moderate yield (4m, 26%).

We then tried to prove whether the sulfonyl fragmentation/ recombination occurred through either a uni- or a multi-molecular pathway. A 1:1 mixture of enallenes 3b and 3f was thus reacted under optimized conditions. We analyzed the crude product by NMR and isolated nearly equimolar amounts of four products, in which aryls and sulfonyl groups were evenly scrambled (Scheme 3). This result shows that the rearrangement is a multimolecular process.

On the basis of literature studies and experimental/ computational studies, we propose the rationale presented in Figure 3 to account for the present complementary cyclization of enallenes.

Monosubstituted allenes have triplet energies that do not match that of the iridium complex. Their redox potentials are beyond those accessible using the present catalyst and visible light.⁶ The oxidation of styryl fragments, especially those with electron-withdrawing substituents, follows suit.⁶ᵃ,⁸ᵃ On the

<figure><img src="image_14.png" /><figcaption>The catalytic cycle with 1,7-allenenes</figcaption></figure>

<figure><img src="image_15.png" /><figcaption>The radical chains with 1,6-allenenes</figcaption></figure>

<figure><img src="image_16.png" /><figcaption>propagation:</figcaption></figure>

<figure><img src="image_17.png" /><figcaption>photocycloaddition via second eT:</figcaption></figure>

<figure><img src="image_18.png" /><figcaption>alternative chain propagation:</figcaption></figure>

<figure><img src="image_19.png" /><figcaption>Figure 3. Proposed reaction mechanism.</figcaption></figure>

contrary, the triplet state of the iridium catalyst could activate the vinylarene arm of substrates through an energy transfer (eT) process.¹² This correlates with the absence of reactivity
observed by replacing the photocatalyst with species that have
triplet energies unable to activate β-styryl units, such as the
popular Ru(bpy)₃²⁺ complex. Upon eT, intermediate ³I can
then evolve through two different pathways, forming either a
six- or a five-membered ring (³II' and ³II, respectively). The
latter cyclization prevails, enabling the formation of vinyl-
idenecyclobutane 2 upon intersystem crossing (ISC). Accord-
ing to density functional theory (DFT) modeling, this stems
from both an easier transition state (TS) and the least stable
exoergonic intermediate (ΔΔG of -6.9 and +24.3 kcal/mol,
respectively, at the M06/def2-TZVP level using DMF as an
implicit solvent).

Analogous activation of the 1,6-enallene gives triplet ³3, for which steric factors disfavor the 4-exo cyclization that would have led to a 2.2.0 bicycle. The alternative formation of a five-membered ring delivers ³III. The cyclization can smoothly take place through a low barrier (ΔG of +6.8 kcal/mol) and thus parallels the results observed with 1,7-alleneses. In ³III the spin density on the allyl group is evenly spread, with a slight preference for the internal carbon atom. The two mono-occupied molecular orbitals are nearly perpendicular in ³III. This likely explains its reduced prowess toward the formation of the expected unobserved [2 + 2] cycloaddition product 4'. However, the N–S bond of ³III is slightly longer than that of ³3 (by +0.008 and +0.0005 Å using def2-SVP and def2-TZVP basis sets, respectively). This makes possible a relatively easy β-fragmentation, which provides ³IV by homolytic N–S bond cleavage. A significant basis set effect on calculated energies was observed for this TS (ΔG of +14.3 and +19.7 kcal/mol using def2-SVP and def2-TZVP, respectively; see the SI for a comparison of the basis sets and the Hartree–Fock contribution to functionals for this step).¹³ Nonetheless, even the least favorable calculated barrier is still viable for a homolytic bond cleavage.

The fate of the two radical fragments of ³IV posed several
hurdles (see the SI for additional, less favorable pathways),
until we considered a chain reaction.¹⁴ Substrate activation,
cyclization, and fragmentation comprise the overall initiation of
the process. The propagation involves the selective addition of
a sulfonyl radical on the C(sp) carbon of a substrate
molecule,¹⁵ affording allyl radical ²V (ΔG = -12.2 kcal/mol)
through a low-lying TS (barrier of +11.9 kcal/mol in ΔG). The
β-fragmentation of ²V occurs through a barrier of +21.4 kcal/
mol in ΔG, and it gives intermediate VI, regenerating the
sulfonyl radical. The former could then undergo a second eT,
providing triplet ³VI, by analogy to the activation of 1 and 3
that is nearly isoenergetic. Triplet ³VI can smoothly evolve into
³VII via 5-exo-trig cyclization (barrier of +8.5 kcal/mol in
ΔG). Product 4 eventually forms by intersystem crossing
(ISC).

An alternative scenario involves a propagation leading
directly to bicycle 4. In this case, allyl radical ²V undergoes a
7-endo-trig cyclization that provides ²VIII upon a relative
barrier of +17.6 kcal/mol in ΔG. The subsequent 4-exo-trig/5-
endo-trig cyclization is the most energy-demanding step of the
pathway (barrier of +24.9 kcal/mol in ΔG), and it gives
bicyclic radical ²IX. The latter could then undergo β-
fragmentation to provide product 4 and regenerate the sulfonyl
radical. This step has a lower barrier compared with the
analogous N–S bond cleavage taking place on ³III (ΔΔG
= –3.4 kcal/mol). Overall, the propagation of this chain reaction
has a largely negative ΔG (–23.6 kcal/mol). All of its steps are

exoergonic and, moreover, progressively more so. This should
further increase the easiness of the propagation.

Starting from ²V, the highest energy TS of this manifold is
just 0.5 kcal/mol lower in energy than that of the joint radical/
photochemical mechanism, suggesting that the competition
might be too close to call. The chain generating VI has a less
favorable ΔG (−7.3 kcal/mol) than that directly affording 4
(−23.6 kcal/mol). This gap, coupled to the requirement of a
second excited ³Ir species to afford the product,⁸ᵃ¹⁶ seems to
favor the odds of an entirely free-radical pathway.

In sharp contrast with the β-fragmentation of the C–S bond
that is a routine tool in radical sequences, it is worth noting
that of α-sulfonamidoyl radicals has very few precedents.¹⁷
These are limited at the present to processes promoted by tin
hydrides, which, furthermore, do not allow reincorporation of
the sulfonyl fragment in the final product.

In conclusion, we reported the synthesis of two comple-
mentary families of 3.2.0 bicycles from enallenes. Both
reactions show remarkable regio- and diastereocontrol,
affording complex scaffolds under mild conditions. Mechanistic
studies point out two orthogonal pathways that took place
under identical conditions, namely, a [2 + 2] photo-
cycloaddition versus a radical chain indirectly initiated by a
photoexcited iridium complex. Although catalytic pathways
and innate chains often compete in visible-light-promoted
processes,¹⁸ we are unaware of synthetic methods in which
they are similarly interconnected.

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ASSOCIATED CONTENT

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Supporting Information

The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02193.

Experimental procedures, synthesis of reagents, charac-
terization of products, modeling data, X-ray crystallog-
raphy data, and copies of NMR spectra (PDF)

Accession Codes

CCDC 2009276-2009278 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

<figure><img src="image_22.png" /></figure>

AUTHOR INFORMATION

Corresponding Author

Giovanni Maestri – Department of Chemistry, Life Sciences and Environmental Sustainability, Università di Parma, 43124 Parma, Italy; orcid.org/0000-0002-0244-8605; Email: giovanni.maestri@unipr.it

Authors

Andrea Serafino – Department of Chemistry, Life Sciences and Environmental Sustainability, Università di Parma, 43124 Parma, Italy

Davide Balestri – Department of Chemistry, Life Sciences and Environmental Sustainability, Università di Parma, 43124 Parma, Italy; orcid.org/0000-0003-3493-9115

Luciano Marchiò – Department of Chemistry, Life Sciences and Environmental Sustainability, Università di Parma, 43124 Parma, Italy
**Max Malacia** — *Faculty of Science and Engineering, CNRS, Institut Parisien de Chimie Moléculaire (UMR CNRS 8232), Paris 75252 Cedex 05, France; orcid.org/0000-0002-3563-3508*

**Etienne Derat** — *Faculty of Science and Engineering, CNRS, Institut Parisien de Chimie Moléculaire (UMR CNRS 8232), Paris 75252 Cedex 05, France*

Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02193

## Notes

The authors declare no competing financial interest.

## ACKNOWLEDGMENTS

This work has benefited from the equipment and framework of the COMP-HUB Initiative, funded by the “Departments of Excellence” program of the Italian Ministry for Education, University and Research (MIUR, 2018-2022). We also acknowledge the support from UniPR, UPMC, and CNRS. Use of modeling facilities was provided by ICSN-CNRS, Gifs/Yvette, France.

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(14) For recent examples of radical chains in visible-light-promoted processes, see: (a) Lubbesmeyer, M.; Mackay, E. G.; Raycroft, M. A. R.; Elfert, J.; Pratt, D. A.; Studer, A. Base-Promoted C—C Bond Activation Enables Radical Allylation with Homoallylic Alcohols. *J. Am. Chem. Soc.* **2020**, *142*, 2609. (b) Voutyritsa, E.; Kokotos, C. G. Green Metal-Free Photochemical Hydroacylation of Unactivated Olefins. *Angew. Chem., Int. Ed.* **2020**, *59*, 1735. (c) Petzold, D.; Singh, P.; Almqvist, F.; König, B. Visible-Light-Mediated Synthesis of β-Chloro Ketones from Aryl Cyclopropanes. *Angew. Chem., Int. Ed.* **2019**, *58*, 8577. (d) Felpin, F. X.; Sengupta, S. Biaryl synthesis with arenediazonium salts: cross-coupling, CH-arylation and annulation reactions. *Chem. Soc. Rev.* **2019**, *48*, 1150.

(15) Liu, L.; Ward, R. M.; Schomaker, J. M. Mechanistic Aspects and Synthetic Applications of Radical Additions to Allenes. *Chem. Rev.* **2019**, *119*, 12422.

(16) Multiphoton processes are statistically challenging; see (a) Marchini, M.; Bergamini, G.; Cozzi, P. G.; Ceroni, P.; Balzani, V. Photoredox Catalysis: The Need to Elucidate the Photochemical Mechanism. *Angew. Chem., Int. Ed.* **2017**, *56*, 12820. (b) Ghosh, I.; Bardagi, J. I.; König, B. Reply to "The Need to Elucidate the Photochemical Mechanism. Angew. Chem., Int. Ed.* **2017**, *56*, 12822. (c) Chatterjee, A.; König, B. Birch-Type Photoreduction of Arenes and Heteroarenes by Sensitized Electron Transfer. *Angew. Chem., Int. Ed.* **2019**, *58*, 14289. (d) Connell, T. U.; et al. The Tandem Photoredox Catalysis Mechanism of $[Ir(ppy)_2(dtb-bpy)]^+$ Enabling Access to Energy Demanding Organic Substrates. *J. Am. Chem. Soc.* **2019**, *141*, 17646. A review: (e) Glaser, F.; Kerzig, C.; Wenger, O. S. Multi-Photon Excitation in Photoredox Catalysis: Concepts, Applications. *Angew. Chem., Int. Ed.* **2020**, *59*, 10266.

(17) (a) Zhang, H.; Hay, B. E.; Geib, S. J.; Curran, D. P. Radical Cyclizations of Cyclic Ene Sulfonamides Occur with β-Elimination of Sulfonyl Radicals to Form Polycyclic Imines. *J. Am. Chem. Soc.* **2013**, *135*, 16610. (b) Darmency, V.; Renaud, P. Alkylation of Ethyl Pyruvate via Reductive Coupling of Alkenes and Ethyl 2-(Benzenesulfonylamino)acrylate. *Chimia* **2005**, *59*, 109. (c) Cossy, J.; Cases, M.; Gomez Pardo, D. Approaches to a synthesis of α-kainic acid. *Tetrahedron* **1999**, *55*, 6153.

(18) For meaningful discussions, see: (a) Cismesia, M. A.; Yoon, T. P. Characterizing chain processes in visible light photoredox catalysis. *Chem. Sci.* **2015**, *6*, 5426. (b) Studer, A.; Curran, D. P. Catalysis of Radical Reactions: A Radical Chemistry Perspective. *Angew. Chem., Int. Ed.* **2016**, *55*, 58.