# Monobromination of Cubane 1,4-Diester, A Synthetic Handle for Fluorosulfonylation and Giese-type Reactions

Laly Donnier-Valentin, Julien Legros, C. Fressigne, Daniela Vuluga, Bruno

Linclau, Michaël de Paolis

► To cite this version:

Laly Donnier-Valentin, Julien Legros, C. Fressigne, Daniela Vuluga, Bruno Linclau, et al. Monobromination of Cubane 1,4-Diester, A Synthetic Handle for Fluorosulfonylation and Giese-type Reactions. Organic Letters, In press, 10.1021/acs.orglett.5c00967 . hal-05033584

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# Monobromination of Cubane 1,4-Diester, A Synthetic Handle for Fluorosulfonylation and Giese-type Reactions

Laly Donnier-Valentin,ª Julien Legros,ª Catherine Fressigné,ª Daniela Vuluga,ᵇ Bruno Linclau,ᶜ Mi-chaël De Paolisª,\*

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

**ABSTRACT:** The bromination of the cubane 1,4-diester is described for the first time. The versatility of the C-Br bond for forging C-S and C-C bonds was demonstrated. The fluorosulfonylation reaction allowed the first entry of the cubane in click chemistry illustrated with nucleophiles, electrophiles and alkynes. The grafting of appendages was illustrated with amino acids and dipeptides, enabling the discrimination of the diesters via cyclisation into “fused cubane-lactam” structures.

Bioisosteres are continually sought-after targets as their inclusion in biomolecules may have interesting implications on the metabolic stability, the physico-chemical and biological properties. As initially theorized by Eaton, cubane is a bioisostere of benzene.[1] As such, a large number of cubane-containing molecules are conceivable in order to enhance the biological profile of the corresponding benzene-containing pharmaceutically relevant molecules, or as a 3D-scaffold in drug design.[2] To that end, the inclusion of cubane ideally requires strategies to functionalize the C-H bonds of the scaffold, in order to graft side chains in a bespoke manner. For that purpose, the *ortho* deprotonation of cubane 1,4-diisopropyl diamide was reported by Eaton[3] and later by Bashir-Hashemi,[4] this step needing the combination of a large excess of lithium amide and a Lewis acid to trap the metalated cubyl species with electrophiles.[5] This strategy of metalation and subsequent functionalization was employed by Yagi and Itami to achieve the elegant programmable pallado-catalyzed arylation of amidocubane **1** into **2** then into **3** (Scheme 1A).[6]

Based on the formation of cubyl radicals, photoinduced reactions involving C-H bond homolysis (HAT) opened new methods of scaffold decoration that are more compatible with functional groups.[7] Recently, Nagasawa and Iwabuchi demonstrated the formation of cubyl radicals directly from dimethyl cubane 1,4-diester **4**, the most readily available material, by abstraction of a hydrogen atom (Scheme 1B).[8] Subsequent alkylation with electron-poor olefins proceeded through the photoinduced Giese-type reaction,[9] yielding for example **5** starting from 3 equivalents of **4** to alleviate the difficult formation of cubyl radical since the C-H bonds of the cubane diester are strong (BDE = 103.3 kcal.mol⁻¹).[10] Prior halogenation (bromination or iodination) of the motif should facilitate, by taking advantage of the polarization of the C-X bond, the formation of cubyl radicals. As a matter of fact, the C-Br bond

of the bromocubane 1,4-diester **9** was calculated with BDE value of 78.9 kcal.mol⁻¹. The large difference of energy (24.4 kcal.mol⁻¹) should facilitate the formation of the cubyl radical with the major implication that **9** could thus be employed in a stoichiometric manner, since the concentration of radical species should be higher, and that reaction with various electrophiles should be possible.

**Scheme 1.** State-of-the-art and this work

<figure><img src="image_3.png" /></figure>

In line with the BDE of the C-H bond of **4**, the direct monobromination or -iodination of the cubyl motif is far from trivi-

<footnote>ª Univ Rouen Normandie, INSA Rouen Normandie, Univ Caen Normandie, ENSICAEN, CNRS, Institut CARMEN UMR 6064, F-76000 Rouen, France. michael.depaolis@univ-rouen.fr,</footnote>

<footnote>ᵇ INSA Rouen, PBS, UMR 6270, CNRS, 766801 Saint-Etienne-du-Rouvray, France.</footnote>

<footnote>ᶜ Ghent University, Department of Organic and Molecular Chemistry, Krijgslaan 281-S4, 9000, Ghent, Belgium.
*Supporting Information Placeholder*</footnote>
al. Fokin demonstrated the synthesis of halocubanes, devoid of other functional groups.[11] Matsubara reported the site selective dibromination of 4-deuterated cubane amide 6 into 7, the selectivity relying on the steric and electronic protection of the scaffold and the brominating reagent (Scheme 1C).[12] In a rare showcase of the reactivity of the cubyl C-Br bonds, treatment with organozincate reagents led to 1,3,5-trisubstituted cubane 8.

Herein, we describe the first monobromination of the commercially available cubane 1,4-diester and illustrate the versatility of the C-Br bond through the photoinduced fluorosulfonylation and Giese-type reactions, enabling the grafting of various functional groups to the cubyl motif (Scheme 1D). This aspect is of paramount importance for enabling the cubane motif to fully reach agrochemical and pharmaceutical studies as a bioisostere of benzene.

An assessment of the reactivity of **4** toward brominating reagents in conventional radical conditions (AIBN, heat) confirmed that selectivity would be difficult to attain as **9** was obtained (~30% yield) alongside polybrominated cubane. Fortunately, the photoinduced monobromination was more selective (Scheme 2). Using tetra-n-butylammonium decationstate (TBADT, 0.01 equiv) as a metal-based photocatalyst at rt in combination with 1,3-dibromo-5,5-dimethylhydantoin DBDMH (0.8 equiv), **9** was isolated 52% yield (2 mmol-scale, 67% conversion) with good mass balance after 16 h at 365 nm in CH₃CN in a single reactor (see the SI for detailed optimization).[13] Note that the bromination of cubane 1,4-diester was more effective than the 1,4-diamide and 1,4-dicyano counterparts.[14] Attempts to reach higher conversion with longer reaction time or higher temperature (> 40 °C) were met with the formation of polybrominated products. Furthermore, a synthesis of **9** was developed under stop-flow technique. Thus, acetonitrile solution of **4**, DBDMH and TBADT were exposed to LED irradiation (365 nm) in a coil of 4 mL (C = 0.1 mL) which allowed the preparation of **9** (47% yield, 70% conversion) after 7 h.

<figure><img src="image_4.png" /><figcaption>**Scheme 2.** Photoinduced bromination of **4**</figcaption></figure>

The versatility of **9** was demonstrated with the introduction of a fluorosulfonyl group as a handle for sulfur(vi)-fluoride exchange (SuFEx) click chemistry (Scheme 3).[15a-c] The radical sulfonylation of **9** into **10** was performed with 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO, 2 equiv) in the presence of an iridium (III) catalyst, such as [Ir(dF(CF₃)-ppy)₂(dtbbp)]PF₆, tristrimethylsilylsilanol (0.7 equiv) and K₃PO₄ (2 equiv), which was followed by the fluoration of the cubyl sulfinate with SelectFluor (2 equiv).[15d] Alongside the reduction product **4** (37% yield), fluorosulfonylated cubane **11a** was formed in 52% yield (2-step) with good mass balance (see the SI for the detailed opti-

misation). Importantly, the fluorosulfonylation of **4** failed to deliver **10**, only traces were indeed at best observed.

The reactivity of the cubyl sulfinate **10** was explored by reaction with electrophiles such as hydroxylamine-O-sulfonic acid leading to sulfonamide **11b** in 50% yield (2-step), while alkyl sulfones **11c** (53% yield, 2-step) and **11d** (52% yield, 2-step) were obtained by quenching **10** with methyl iodide and benzyl bromide, respectively.

With **11a** in hand, the grafting of various nucleophiles was demonstrated. Hence, sulfonamide **12a** was obtained in 49% yield by the simple exposure to pyrrolidine (5 equiv) at room temperature. Adding 1-hydroxybenzotriazole (0.15 equiv), tetramethyldisiloxane (2 equiv), a base and operating in DMSO (40 °C) enhanced the yield to 76% while a lower amount of pyrrolidine (1.2 equiv) was employed.[15e] The addition of morpholine to **11a** was performed in similar conditions furnishing the sulfonamide **12b** in 79% yield. N-α-Fmoc-L-lysine was linked to **11a** providing **12c** in 40% yield after the N-Boc protection of the free amino ester, the N-Fmoc deprotection occurring in the reaction conditions. A simpler primary amine, benzylamine, was coupled to **11a** giving sulfonamide **12d** in 88% yield.

Phenol was ligated to the cubyl sulfonyl motif in 76% yield (**12e**) in the presence of Cs₂CO₃.[15f] Cubyl sulfonyl azide **12f** was quantitatively obtained by reaction of **11a** with sodium azide.[15g] The cycloaddition of **12f** was showcased with alkynes and copper(I) thiophene-2-carboxylate catalyst. The azide cycloadded with ethynyl 4-methylbenzene delivering **12fa** in 78% yield as a single regioisomer assessed by 2D NMR spectroscopy. Similarly, ethynyl 4-fluorobenzene and 2-ethynylnaphtalene were reacted with **12f** yielding triazoles **12fb** (82% yield) and **12fc** (84% yield). The cycloaddition of **12f** with 2-methylbut-3-yn-2-ol delivered **12fd** in 89% yield.

We next examined the reactivity of **9** to form C-C bonds by Giese-type reaction. Against the general tendency of working with an excess of bromoalkanes to perform this transformation, a protocol in which **9** is employed as the limiting reagent was devised (Scheme 4). The competitive reduction of the C-Br bond against the C-C bond formation remains challenging. A screening of conditions revealed that 2,6-lutidine and 4,4'-dimethoxybenzophenone, as base and photocatalyst, performed the coupling of **9** in CH₃CN with trifluorocrotonate ester in 44% yield with good mass balance. Equally interesting was the regioselectivity of the coupling reaction as the regioisomer **13a** was obtained alongside the isomer **13a'** in a ratio of 2:1 (44% yield) assessed by ¹⁹F NMR spectroscopy.

The same regioselectivity (rr = 2:1) was noted with trifluorocrotonic acid (**13b,b'**, 50% yield, 55% brsm), demonstrating incidentally that the carboxylate formed during the reaction is not preventing the coupling. Importantly, the two regioisomers can be separated. Amides of the trifluorocrotonic acid were also compatible with the Giese-type coupling displaying the same regioselectivity than the ester and acid counterparts (**13c,c'**, 44% yield, rr = 2:1).[16]

The coupling of ethyl 3-(phenylsulfonyl)acrylate with **9** gave a single regioisomer **13d** bearing the primary alkyl phenylsulfone in 48% yield, the regioselectivity being verified by 2D NMR spectroscopy. Strikingly, while crotonate or acrylonitrile do not react with **9**, heterosubstituted olefins were coupled to **9**.
<figure><img src="image_5.png" /><figcaption>Scheme 3. Photoinduced sulfonylation reaction of 9 and synthetic manipulations <sup>a)</sup></figcaption></figure>

<figure><img src="image_6.png" /><figcaption>Scheme 4. Optimized photoinduced Giese-type reaction of 9</figcaption></figure>

<footnote>a) Reagents and conditions: a) Nucleophile, 1-hydroxybenzotriazole (HOBT), 1,1,3,3,3-pentamethyldisiloxane (TMDS), (iPr)₂NEt, DMSO, 40 °C; b) PhOH, Cs₂CO₃, CH₃CN, rt; c) NaN₃, acetone/H₂O, rt; d) NH₂OSO₃H (4 equiv), H₂O, rt; e) Electrophile (1,5 equiv), DMF, rt; f) Alkyne (1.5-1.7 equiv), copper(I) thiophene-2-carboxylate (CuTC) (10 mol%), PhMe, rt.</footnote>
Hence, phenyl vinylsulfone, *t*-butyl vinylsulfonamide and diethyl vinylphosphonate gave **13e** in 44% yield, **13f** in 44% yield and **13g** in 42% yield, underscoring that olefins activated by inductive effect are efficient partners. The convergent access to cubyl analogues of amino acids is not trivial. Yet, this is particularly important in drugs discovery as the cubyl motif could impact the folding and physico-chemical properties of peptides. While efforts were directed toward the synthesis of cubylglycine,[17] cubyl analogues of phenylalanine are scarce. Actually, a single example of decarboxylative Giese addition of *N*-hydroxyphthalimide derivative of **4** with dehydroalanine was reported by Baran.[18] In contrast, the bromination of **4** paves the way to the grafting of amino ester while preserving the ester moieties that could be discriminated and functionalized in a further stage.

The coupling of **9** with *N*-Ac-*N*-Boc-dehydroalanine methyl ester led to compound **13h** in 43% yield, providing the first access to cubane 1,4-diester connected to methylene imido ester. The *bis*- *N*-Boc-dehydroalanine methyl ester was coupled to **9** in 29% yield (**13i**) while less hindered *N*-phthalimide protected dehydroalanine as well as methyl 2-(*N*- (Boc)-4-methoxybenzamido)acrylate were coupled to **9** in 35% yield (**13j**) and in 48% yield (**13k**).

The protection of the carboxylic acid of the *bis*- *N*-Boc-dehydroalanine is not even necessary, **13l** being isolated in 35% yield, facilitating thus future functionalization.

The coupling of **9** with a more hindered dehydroalanine-containing dipeptide led to **13m** in 36% yield (dr = 6:4). This experiment showcases the late stage cubyl decoration of peptides as long as tertiary amide of dehydroalanines are employed as electrophiles. A secondary amide of dehydroalanine was indeed found to be incompatible with the chemistry while attempting to prepare **13n**.

To illustrate the versatility of the cubyl amino esters **13h**, we prepared a cubyl *δ*-lactam by achieving the discrimination of the 1,4-diester functions (Scheme 5A). To that end, **13h** was deprotected (HCl aq., MeOH, 80°C) into **14**. This step was followed by a simple basic treatment (NaHCO₃, MeOH, 60°C) of the amino acid delivering the “fused cubane-lactam” **15** in excellent yield (> 95%, 2-step) despite the increased strain induced by the C(sp²) carbon at the junction of the two rings.[19]

Note that the cyclization of **16**, obtained by *N*-Boc deprotection of **13i**, into *δ*-lactam **15** first necessitated the *in situ* saponification of the cubyl 1,4-diester functions to proceed. Without water, the diester **16** was recovered unchanged. Furthermore, the discrimination of the carboxylic functions of **15** was performed through a simple sequence, highlighted in Scheme 5B, involving the bis esterification (HCl conc., MeOH, 40°C), solely followed by evaporation of the volatiles and exposure of **17** to water at room temperature (CD₃OD, 48 h) for the selective hydrolysis of the methyl cubyl ester into **18** (>95% yield).

As noted earlier, secondary dehydroalanines are not compatible with the coupling conditions. To overcome the limitation, the formation of secondary amide was demonstrated from **13l** by coupling with glycine (HATU, CH₂Cl₂) supplying **19** in 61% yield (Scheme 5C).

### Scheme 5.

<figure><img src="image_7.png" /></figure>

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

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

The first selective monobromination of cubane 1,4-diester **4** was demonstrated, paving the way for further functionalization of the scaffold. Among the many conceivable developments now at disposal, the formation of C-S bonds was demonstrated through photoinduced sulfonylation reactions providing the first entry of cubane into the field of the click chemistry. With different physicochemical and metabolic properties from the phenyl analogue, the fluorosulfonyl cubane **11a** is a stable electrophilic warhead ready for ligation.

Complementary to the pioneering study of Nagasawa and Iwabuchi, the Giese-type reaction of **9** gave unprecedented access to 2-alkyl cubane 1,4-diester connected to amides, acids, sulfonamides, sulfones, trifluoromethanes, phosphonates and peptides in two steps from commercially available material. Taking advantage of the amino acid appendage, the cubyl 1,4-diester functions were discriminated via cyclisation into “fused cubane-lactam” structures. Keeping in mind that one equivalent of bromocubane **9** is employed, the fact that the C-S and C-C bonds are formed in spite of the reduction process is noteworthy considering the steric hindrance of the cubane 1,4-diester.

## ASSOCIATED CONTENT

### Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

### Supporting Information Statement

The Supporting Information is available free of charge on the ACS Publications website.

General procedure and characterizations of each compounds, as well as optimization of the procedure, copies of ¹H, ¹³C NMR spectra and computational details.

## AUTHOR INFORMATION
Corresponding Author

* Michael.depaolis@univ-rouen.fr, ORCID 0000-0001-8139-3544

Authors

Laly Donnier-Valentin, Julien Legros, Catherine Fressigné, Michaël De Paolis – Univ Rouen Normandie, INSA Rouen Normandie, Univ Caen Normandie, ENSICAEN, CNRS, Institut CARMEN UMR 6064, F-76000 Rouen, France

Daniela Vuluga – INSA Rouen, PBS, UMR 6270, CNRS, 76801 Saint-Etienne-du-Rouvray, France

Bruno Linclau – Ghent University, Department of Organic and Molecular Chemistry, Krijgslaan 281–S4, 9000 Ghent, Belgium

ACKNOWLEDGMENT

We are very grateful to the ANR (CERES, ANR-21-CE07-0048)) for a fellowship to L. D-V. This work has been partially supported by Université de Rouen Normandie, INSA Rouen Normandie, Centre National de la Recherche Scientifique (CNRS), Labex SynOrg (ANR-11-LABX-0029), Carnot Institute I2C, the graduate school for research XL-Chem (ANR-18-EUR-0020 XL CHEM) and by Région Normandie. The authors gratefully acknowledge the European Regional Development Fund. We thank the CRIANN for the computational resources. B.L. acknowledges the Research Foundation Flanders (FWO, Belgium) for an Odysseus Type I grant (G0F5621N).

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Wang, J.; Lundberg, H.; Asai, S.; Martín-Acosta, P.; Chen, J. S.; Brown, S.; Farrell, W.; Dushin, R. G.; O'Donnell, C. J.; Ratnayake, A. S.; Richardson, P.; Liu, Z.; Qin, T.; Blackmond, D. G.; Baran, P. S. Kinetically guided radical-based synthesis of C(sp3)–C(sp3) linkages on DNA. *Proc. Natl. Acad. Sci. U.S.A.* **2018**, *115*, DOI 10.1073/pnas.1806900115.

Previous example of fused cubane: Nagasawa, S.; Hosaka M.; Iwabuchi, Y. ortho-C–H Acetoxylation of Cubane Enabling Access to Cubane Analogues of Pharmaceutically Relevant Scaffolds. *Org. Lett.*, **2021**, *23*, 8717–8721.

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