O-, N- and C-bicyclopentylation using thianthrenium reagents

Rigid 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs) are linear bioisosteres for para-substituted benzene rings in drug development and can lead to an improved pharmacokinetic profile. The construction of BCPs commonly requires the cumbersome use of labile [1.1.1]propellane in solution, and more stable reagents do not show the versatile reactivity of propellane itself. Here we report stable thianthrenium-based BCP reagents for practical O-, N- and C-alkylation reactions that expand the scope of bicyclopentylation beyond that of any other reagent, including [1.1.1]propellane. The redox and stereoelectronic properties of the thianthrene scaffold are relevant for both the synthesis of the BCP-thianthrenium reagents via strain release as well as their subsequent reactivity. The weak exocyclic C–S bond can undergo selective mesolytic cleavage upon single-electron reduction to produce BCP radicals that engage in transition metal-mediated C–O, C–N and C–C bond formations, even at a late stage of multistep reactions with a wide variety of functional groups present. 1,3-Disubstituted bicyclo[1.1.1]pentanes are linear bioisosteres for para-substituted benzene rings; however, the lack of practical reagents for the introduction of bicyclopentane currently impedes their application, especially in drug development. Now, stable thianthrenium-based bicyclopentane reagents are reported and their use in O-, N- and C-alkylation reactions demonstrated.

practical reagent of similar or greater utility could increase the incorporation of BCP substituents to benefit from their desirable properties, but such a reagent has not yet been reported. Several useful BCP-based reagents, such as Grignard reagents 14 , iodides 6,15,16 , boronates 7,12,17 and redox-active esters 18 , have been developed. Although most of these reagents can successfully engage in C-C bond formations, none has yet reached the generality in reactivity of [1.1.1]propellane 4 , and they often lack stability for storage 19 or require multiple steps for preparation 18 . Furthermore, neither BCP-based reagents nor [1. 1.1]propellane are yet available for the synthesis of aryl bicyclo[1.1.1]pentyl ethers.
Sulfonium salts can act in nature as efficient alkylation reagents 20 . Similarly, chemists have used sulfonium salts in alkylation reactions, but the transfer of tertiary alkyl groups, such as bicyclopentyl, remains unknown. We have previously reported on the reactivity of arylthianthrenium salts, which can expand the chemical space of (pseudo)halides, and attributed their unusual properties to the thianthrene scaffold [21][22][23][24][25][26] . Based on single electron reactivity, a high reduction potential, and the ability to function as a good leaving group and readily engage in radical chemistry, we have devised a strategy for the synthesis of BCP-thianthrenium salts that function Article https://doi.org/10.1038/s44160-023-00277-8 copper catalysis has been used successfully in thianthrene (TT) 27 and BCP 10 chemistry, we also introduce here a previously unreported photoredox-mediated nickel-catalysed cross-coupling reaction with alkylthianthrenium salts.
as stable and versatile alkylating reagents. Distinct from conventional alkylsulfonium salts, thianthrenium-substituted BCPs can engage in radical chemistry that productively combines photoredox catalysis with transition metal-mediated bond formation. Although a MeCN, 35

Development of stable thianthrenium-based BCP reagents
The CF 3 BCP-TT + salt 3 was synthesized by the addition reaction between the trifluoromethylthianthrenium reagent 1 (ref. 28 ) and       Tables 15-18) and consistent with a measured quantum yield of Φ = 16 (Fig. 1d). The stability of the thianthrenium radical cation sets TT apart from conventional sulfides. In contrast to volatile and thermally unstable propellane 29 , compound 3 is a non-hygroscopic, free-flowing powder with a melting point of 150 °C that can be stored under ambient conditions without observable decomposition for at least 1 year.
Differential scanning calorimetry analysis confirmed that heating 3 to 170 °C did not lead to exothermic decomposition, which attests to its favourable safety properties. Although compound 3 is synthesized from [1.1.1]propellane, the practitioner interested in BCP substitution would not be required to handle the unstable reagent if 3 were produced centrally and distributed. Based on the same strategy, we prepared nonafluorobutyl-BCP-TT + salt 4 from 2 in 73% yield (Fig. 1a).
In addition, this class of compound can be accessed by an alternative mechanism from S-substituted TT-based reagents, as shown by the reaction of a persistent thianthrenium radical cation with [1.1.1] propellane to afford the cyano-substituted BCP reagent 5 (Fig. 1b),   [16][17][18][19][20][21]. The ensuing chemoselective mesolytic cleavage of the exocyclic BCP-thianthrene C-S bond can be rationalized by both a notably longer exocyclic C-S bond compared with the endocyclic C-S bonds within the TT scaffold, as determined by X-ray crystallographic analysis of 3 (Fig. 1d), and barrierless homolysis of the exocyclic C-S bond upon single electron reduction of 3, as supported by DFT calculations ( Supplementary  Figs. 14 and 15). The resulting synthetically useful BCP radical is thus readily generated in situ by functional group-tolerant photoredoxmediated SET. Oxidative ligation of the BCP radical to transition metals in medium oxidation states, such as Cu(II), obtained by reductive quenching of the excited photocatalyst, or Ni(II), obtained by oxidative addition to aryl halides, can provide high-valent transition metal-BCP complexes. Ensuing facile reductive elimination reactions in which the BCP scaffold attaches to functional groups should be achievable from such high-valent complexes (Fig. 1e).

Scope of N-bicyclopentylation
An analogous strategy was successful for the bicyclopentylation of N-nucleophiles (Table 2). Compared with the published N-alkylation reactions with propellane 8,10,[33][34][35][36] , N-bicyclopentylation with 3-5 and 8 has much greater scope. Medicinally relevant substructures, such as indoles (35 and 39) and pyrrole (38), are compatible with our protocol, as are 4-azaindole (36), benzotriazole (37), indazole (40), imidazoles (41 and 42), pyrazoles (45 and 46) and carbazole (47). Moreover, the methodology is not limited to N-heterocycles, as phthalimide (48), dihydroquinolinone (50), β-lactam (51), amides (52 and 53) and sulfonamide (55) also work well in this transformation. Aniline (56), 2-aminopyridines (54 and 58) and 5-aminopyrazole (49) also undergo C-N coupling in good yields. Notably, 2-aminopyrrolo[2,1f] [1,2,4]triazine (57), which is found in the structure of remdesivir 37 (an antiviral agent against COVID-19), can be functionalized efficiently. By slightly modifying the conditions, the scope of the reaction could be further extended to benzylamines (59) and alkylamines (60). As in the corresponding ether bond formation, broad functional group tolerance, even for redox-active aryl iodides (40), enables late-stage modification of various pharmaceutically relevant molecules in the drug discovery process (38, 39, 43, 50, 54, and 55), as shown in Table  2. Basic, electron-rich tertiary amines are not tolerated, potentially a consequence of their single electron oxidation by excited photoredox catalysts. When more than one N-nucleophile is present, functionalization of the more acidic position proceeds chemoselectively (for example, 55). Both C-O and C-N bond-forming reactions are, in principle, catalytic in the transition metal, yet the use of about half an equivalent of copper afforded higher yields. Although a lower copper loading is possible, the reduced yield is, in our opinion, not justifiable given the low cost of simple copper salts compared with the cost of the other complex starting materials employed in these transformations.

Scope of C-bicyclopentylation
Reagents 3-5 can, beyond C-heteroatom cross-coupling with copper, also participate in metallophotoredox catalysis with nickel catalysts for reductive C-C cross-coupling reactions with (hetero) aryl bromides ( Table 3). The synergistic cooperation of nickel and photoredox catalysis with thianthrenium salts has not been reported before. Carbon-carbon cross-coupling reactions of iodo-BCPs 9 , BCP Grignard reagents 14 , BCP-boronates 7,12,17 and BCP redox-active esters 18 have been developed previously, but not with reagents as synthetically convenient as 3-5. The mechanism from 3-5 could proceed through a Ni(0)-Ni(II)-Ni(III)-Ni(I) cycle with oxidative ligation of the BCP radical to a Ni(II)-aryl complex obtained by the oxidative addition of Ni(0) to an aryl bromide, with ensuing reductive C-C elimination from a putative high-valent Ni(III) complex 38 , 82 and 87). The most prominent side reaction for electron-rich aryl bromides is protodebromination.

Synthetic applications
To highlight the synthetic utility of the methodology, we performed several transformations on cyanobicyclo[1.1.1]pentyl ether 30 (Fig.  2). For example, the reduction of 30 with NiCl 2 and NaBH 4 afforded alkylamine 88 in 70% yield. In addition, the cyano group was converted into BCP ester 89 and BCP carboxylic acid 90. Finally, BCP amine 91 was prepared from 30 by Curtius rearrangement.

Conclusion
We have reported here a storable, thianthrenium-based class of BCP transfer reagents that can afford valuable small molecules that are in part currently inaccessible by other methods. We anticipate that the commercial availability of a stable and readily employed reagent would enable practitioners, for example, in the pharmaceutical industry, to introduce the promising BCP substituent substantially more easily into small molecules of interest than is possible today.

General procedure for Ni-catalysed reductive C-C coupling of 3-5 with aryl bromides
Under nitrogen atmosphere, a 4-ml borosilicate vial equipped with a magnetic stirring bar was charged with the aryl bromide (0.200 mmol, 1.00 equiv.), 3-5 (0.300 mmol, 1.50 equiv.), 4CzIPN (5 mg, 6 µmol, 3 mol%), Ni(dtbbpy)Br 2 (19.4 mg, 40.0 µmol, 20.0 mol%), anhydrous DMA (2.0 ml, c = 0.10 M) and Et 3 N (83 µl, 61 mg, 0.60 mmol, 3.0 equiv.). The vial was sealed with a septum cap. The mixture was then stirred for 10 min at 25 °C, placed 5 cm away from two blue LEDs (Kessil A160WE Tuna Blue (460 nm), LED lighting, 40 W) and irradiated for 16 h while maintaining the temperature at approximately 30 °C by cooling with a fan. After irradiation, EtOAc (6 ml) was added to the mixture, which was then washed with brine (2 × 3 ml). The organic phase was dried over Na 2 SO 4 , filtered and the solvent removed under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the desired product.

Data availability
The data reported in this paper are available in the main text or the Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2075820 (compound 3) and 2172887 (compound 5). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.