A BICYCLOPENTYL THIANTHRENIUM COMPOUND, PROCESS FOR PREPARING THE SAME AND THE USE THEREOF

Abstract

The present inventions discloses a novel bicyclopentyl thianthrenium compound referred to as TT-BCP.sup.+X.sup., a process for preparing the same and the use thereof for bicyclopentylating organic compounds.

Claims

1. A thianthrene derivative of the Formula (I): ##STR00031## wherein R.sup.1 to R.sup.8 may be the same or different and are each selected from hydrogen, halogen, a C.sub.1 to C.sub.6 alkyl group, which is optionally substituted by at least one halogen, or a OC.sub.1 to C.sub.6 alkyl group, wherein R.sup.P represents CF.sub.3 or ON and wherein X.sup. is an anion, selected from F.sup., Cl.sup., triflate.sup., BF.sub.4.sup., SbF.sub.6.sup., PF.sub.6.sup., ClO.sub.4.sup., 0.5 SO.sub.4.sup.2 or NO.sub.3.

2. A thianthrene derivative of the Formula (I) as claimed in claim 1 wherein, in Formula (I), R.sup.1 to R.sup.8 may be the same or different and are each selected from hydrogen, Cl or F, R.sup.P is as defined in claim 1 and X.sup. is an anion as defined in claim 1.

3. A thianthrene derivative of the Formula (I) as claimed in claim 1 wherein, in Formula (I), R.sup.1 to R.sup.8 are each hydrogen, R.sup.P is as defined in claim 1 and X.sup. is an anion as defined in claim 1.

4. A thianthrene derivative of the Formula (I) as claimed in claim 1 wherein, in Formula (I), R.sup.1 to R.sup.8 are each hydrogen, R.sup.P is as defined in claim 1 and X.sup. is an anion selected from triflate or BF.sub.4.sup..

5. For a process comprising transferring a bicyclopentyl group to an organic compound selected from phenols, nucleophiles and aryl halides in the presence of a transfer agent, wherein the transfer agent is a bicyclopentyl thianthrenium compound of the Formula (I) as claimed in claim 1.

6. A process comprising transferring a bicyclopentyl group in the presence of a photocatalyst and a transfer agent in a transition-metal-mediated bond formation to an organic compound selected from aryl halides, phenols and nucleophilic compounds, wherein the transfer agent is a bicyclopentyl thianthrenium compound of the Formula (I) as claimed in claim 1.

7. The process according to claim 6, wherein the organic compound is an N nucleophile.

8. The process according to claim 6, wherein the organic compound is substituted by at least one group selected from hydroxyl, aldehyde, carboxylic acid ester, olefin, amino, amido, sulfonamido, halogen selected from bromo, fluoro, and chloro.

Description

[0037] The invention is further illustrated by the attached Figures and Examples. In the Figures, the respective Figure shows:

[0038] FIGS. 1A and 1B: Bicyclo [1.1.1]pentane thianthrenium salts;

[0039] FIGS. 2A and 2B: Substrate scope for Cu-catalyzed CO cross coupling of 3, 4, and 5 with phenols;

[0040] FIGS. 3A and 3B: Substrate scope for CN cross coupling of 3, 4, 5, and 8 with N-nucleophiles;

[0041] FIGS. 4A and 4B: Substrate scope for Ni-catalyzed reductive CC cross coupling of 3, 4, and 5 with (het)aryl bromides.

[0042] FIG. 5: Synthetic utility of the methodology.

[0043] In more detail, FIG. 1 illustrates: [0044] a: Synthesis of CF.sub.3BCP-TT.sup.+ BF.sub.4.sup. (3) and .sup.nC.sub.4F.sub.9BCP-TT.sup.+ BF.sub.4.sup. (4) reagents. The general reaction conditions are as follows: CF.sub.3-TT.sup.+ OTf.sup. (1.0 equiv), [1.1.1]propellane (1.2 equiv.), MeCN (0.14 M), purple LED (390 nm), 35 C., 4 h, followed by aqueous workup with NaBF.sub.4 (10% w/w). [0045] b: Synthesis of CNBCP-TT.sup.+ BF.sub.4.sup. (5) salt. Conditions: [1.1.1]propellane (1.0 equiv.), thianthrenium tetrafluoroborate (TT.sup.+ BF.sub.4.sup.) (2.0 equiv.), TMSCN (2.0 equiv.), CuCN (40 mol %), DCM (0.20 M), 0-20 C., 12 h. [0046] c: Synthesis of TsBCP-PXT.sup.+ BF.sub.4.sup. (8) salt. Conditions: 1) 6 (1.0 equiv), [1.1.1]propellane (1.2 equiv.), MeCN (0.12 M), blue LED (460 nm), 30 C., 12 h; 2) mCPBA (1.0 equiv), DCM (0.3 M), 0-25 C., 10 min; 3) Tf.sub.2O (1.1 equiv.), DCM (0.12 M), 45-25 C., 1 h. [0047] d: Proposed mechanism of 3 formation proceeding through a radical chain propagation and crystal structure of 3. Thermal ellipsoids are drawn at the 50% probability level. Hydrogen atoms and counterion have been omitted for clarity. [0048] e: Proposed mechanism for the cross-coupling of BCP-TT.sup.+ salts enabled by the photoredox catalysis and transition metal catalysis. [0049] f: Synthetic utility of BCP-TT.sup.+/PXT.sup.+ salts. TT, thianthrene; CF.sub.3, trifluoromethyl; TMS, trimethylsilyl; Ts, 4-toluolsulfonyl; PXT, phenoxathiin; PC, photoredox catalyst; Ar, aryl; Het, hetero; BCP, bicyclo[1.1.1]pent-1-yl.

[0050] As shown in the Figures, a practical synthesis of the CF.sub.3BCP-TT.sup.+ salt 3 was accomplished by an addition reaction between the trifluoromethylthianthrenium reagent 1 and [1.1.1]propellane (FIG. 1a). All experimental observations and DFT calculations are consistent with a radical chain transfer mechanism that includes irradiation of 1 with purple LEDs at a wavelength transparent to 3 to induce homolytic SCF.sub.3 cleavage, followed by radical addition of CF.sub.3 radical to [1.1.1]propellane to form putative BCP radical A. Subsequent chain propagation by TT radical cation abstraction from 1 by A through a low lying transition state TS is supported by DFT and consistent with a measured quantum yield of =16 (FIG. 1d). The stability of the TT radical cation sets thianthrene apart from conventional sulfides. In contrast to volatile and thermally unstable propellane, compound 3 is a non-hygroscopic, free-flowing powder that can be stored under ambient conditions without observable decomposition for at least one year, and a melting point of 150 C. A differential scanning calorimetry (DSC) analysis confirmed that heating of 3 up to 170 C. is not accompanied by any exothermic decomposition process, which attests to its favorable safety properties. Compound 3 is made from synthetically involved [1.1.1]propellane, yet, 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.sup.+ 4 from 2 in 73% yield. In addition, a synthesis other than radical chain transfer from S-substituted thianthrene-based reagents can access the novel compound class, as shown by a synthesis from the persistent thianthrenium radical cation to afford the cyano-substituted BCP reagent 5 (FIG. 1b) and a stepwise synthesis of 4-toluolsulfonyl BCP-phenoxathiin (PXT) reagent 8 starting from thiosulfonate 6 (FIG. 1c). It is expected that the cationic BCP-TT.sup.+ 3-5 are easily reduced by a single electron either by the excited state of a photoredox catalysts or by a reduced photoredox catalyst obtained through reductive quench from the excited state. We have observed reductive quenching of the excited photocatalyst Ir[(dtbbpy)ppy.sub.2]PF.sub.6 by Stern-Volmer quenching studies, for example in the presence of copper (I) to generate putative Ir(II) for SET reduction of 3 (E.sub.1/2 of 3=1.4 V; [Ir.sup.III/Ir.sup.II]=1.5 V, both versus SCE in MeCN. The ensuing chemoselective mesolytic cleavage of the exocyclic BCP-thianthrene CS bond can be rationalized by both a significantly longer exocyclic CS bond when compared to the endocyclic CS bonds within the TT scaffold as determined by X-ray crystallographic analysis of 3 (FIG. 1d), and barrierless homolysis of the exocyclic CS bond upon single electron reduction of 3 as supported by DFT. The resulting synthetically useful BCP radical is thus readily available in situ by functional-group-tolerant photoredox-mediated SET. Oxidative ligation of the BCP radical to transition metals in medium oxidation states, such as Cu(II) obtained through the reductive quench from the excited photocatalyst, or Ni(II) obtained from oxidative addition into aryl halides, can access high-valent transition metal BCP complexes. Ensuing facile reductive elimination reactions to attach the BCP scaffold to several atoms should be achievable from such high-valent complexes (FIG. 1e).

[0051] As shown in FIG. 2, the general reaction conditions for Cu-catalyzed CO cross coupling of 3 or 5 with phenols are as follows: phenol (0.15 mmol, 1.0 equiv), 1 or 2 (2.0 equiv.), Ir[(dtbbpy)(ppy).sub.2]PF.sub.6 (2 mol %), CuCl (50 mol %), DIPEA (2.0 equiv.), DCE (0.05 M), blue LED (40 W), 30 C., 16 h. .sup.aDCM (0.05 M) was used instead. .sup.b1 (3.0 equiv.) and CuCl (100 mol %) were used.

[0052] Aryl bicyclo[1.1.1]pentyl ethers have potential as bioisosteres for diaryl ether derivatives that are common structural motifs in natural and synthetic pharmaceutically important compounds. However, no synthesis to construct aryl BCP ethers is currently documented. Reagents 3-5 can successfully be employed in the metallaphotoredox-catalyzed alkylation of phenols with sub-stoichiometric amounts of copper salts to access the previously unknown class of aryl BCP ethers (Table 1). The reactions exhibits broad scope, and proceeds efficiently with phenols bearing electron-neutral, -rich, and -poor substituents (e.g. 9, 11, and 17, respectively), as well as ortho-substituted phenols (e.g. 13, 16, 18). Synthetically useful functional groups such as hydroxy (11), ester (12, 15, 23, 29), amide (15), aldehyde (16), 2-oxazolidone (20), ketone (21), lactam (24), alkynyl (25), alkenyl (27), and even tertiary amines (18) are tolerated, highlighting the mildness of the reaction conditions. Aryl chlorides (13, 24, 26) and bromides (14, 17) are tolerated, resulting in potential reactive sites for functional group interconversion. Similarly, Bpin (19) and TIPS (25) groups are tolerated, which are well known as nucleophilic coupling partners for Suzuki and Hiyama cross coupling, respectively. In addition, Lewis basic heterocycles, including pyridine (10) and thiazole (12), that can be a liability in transition metal catalyzed coupling reactions, do not inhibit the desired cross coupling reactivity. The reaction is chemoselective with respect to N-nucleophiles (e.g. 15, vide infra). Due to the large functional-group compatibility, late-stage functionalization of drug molecules, such as triclosan (13), benzbromaron (17), sinomenine (18), and chlorophene (26) are accessible. Combined with thianthrene-mediated late-stage aromatic CH hydroxylation, we have realized a multistep site selective CH/bicyclopentyloxylation of small-molecule pharmaceuticals and pesticides, such as flurbiprofen methyl ester (23), diclofenac amide (24), and pyriproxyfen (28).

[0053] As illustrated in FIG. 3, an analogous strategy was successful for bicyclopentylation of N-nucleophiles (Table 2). Distinct from published procedures for N-alkylation reactions with propellane, bicyclopentylation with 3-5 and 8 proceeds with a larger scope with respect to the nitrogen nucleophile. Medicinally relevant sub-structures such as indoles (35, 39) and pyrrole (38) are compatible with our protocol, as are 4-azaindole (36), benzotriazole (37), indazole (40), imidazoles (41, 42), pyrazoles (45, 46), and carbazole (47). Moreover, the methodology is not limited to N-heterocycles, examples of phtalimide (48), dihydroquinolinone (50), -lactam (51), amides (52, 53), and sulfonamide (55) work well in this transformation. Aniline (56), 2-aminopyridines (54, 58), and 5-amino pyrazole (49) can also undergo CN coupling in good yields. Notably, 2-aminopyrrolo[2,1-f][1,2,4]triazine (57) which is found in the structure of remdesivir (against COVID-19) can be functionalized efficiently. By slightly modifying the reaction conditions, the scope could be further extended to benzylic amines (59) and alkyl amines (60). As in the corresponding ether bond formation, large functional group tolerance, even for redox-active aryl iodides (40), enables late-stage modification of various pharmaceutically relevant molecules in drug discovery process (38, 39, 43, 50, 54, 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 nitrogen nucleophile is present, functionalization of the more acidic position proceeds chemoselectively (e.g. 55). Both CO and CN bond forming reactions are, in principle, catalytic in transition metal, yet, use of about half an equivalent of copper afforded the highest yields. Although reduction of the copper loading is possible, the lower yield is, in our opinion, not justifiable given the low cost of the simple copper salts when compared to the cost of the other complex starting materials employed in these transformations.

[0054] In addition to its simple synthesis and stability, reagents 3-5 can, beyond C-heteroatom cross coupling with copper, also participate in metallophotoredox catalysis with nickel catalysts for reductive CC cross coupling reactions with (het)aryl bromides (FIG. 4). Synergistic cooperation of nickel catalysis and photoredox catalysis with thianthrenium salts has not been reported before. Carbon-carbon cross coupling reactions of iodo-BCPs, BCP Grignard reagents, BCP-boronates, and BCP redox active esters have been developed previously but not with a reagent as synthetically convenient as 3-5. A mechanism from 3-5 could proceed through a Ni(0-II-III-I) cycle with oxidative ligation of the BCP radical to a Ni(II) aryl complex obtained by oxidative addition of Ni(0) to an aryl bromide, with ensuing reductive CC elimination from a putative high-valent Ni(III) complex. The cross-coupling of electron poor arenes (65, 66, 72, 83) was successful; engaging electron-rich arenes resulted in lower yields (81). Under the current reaction conditions, a variety of functional groups could be tolerated such as ketones (65), amides (66, 67), esters (71, 86, 87), nitriles (72), heteroarenes (74, 76, 80, 82, 85-87), and 1-3 sulfonamides (81, 82, 86). The reactive functional groups Bpin (78), and triflate (83) are also well tolerated. The synthetic utility of the strategy was further exemplified by the functionalization of heteroaromatic bromides (73, 79, 84) and pharmaceuticals (77, 82, 87). The most prominent side reaction for electron-rich aryl bromides is proto-debromination.

[0055] As shown in FIG. 4, the general reaction conditions are as follows: Aryl halide (0.20 mmol, 1.0 equiv), 3-5 (1.5 equiv.), 4CzIPN (3 mol %), Ni(dtbbpy)Br.sub.2 (20 mol %), Et.sub.3N (3.0 equiv.), DMA (0.1 M), blue LED (460 nm, 40 VA, 30 C., 16 h. .sup.aNi(dtbbpy)Cl.sub.2 (20 mol %) was used as catalyst.

[0056] To highlight the synthetic utility of the methodology, the inventors performed several transformations on cyanobicyclo[1.1.1]pentylether 30 (FIG. 5). For example, reduction of 30 with NiCl.sub.2 and NaBH.sub.4 afforded alkyl amine 88 in 70% yield. In addition, the cyano group was converted to BCP ester 89 and BCP carboxylative acid 90. Finally, BCP amine 91 was prepared from the 30 via Curtius rearrangement.

[0057] As shown in FIG. 5, the synthetic transformations of cyanobicyclo[1.1.1]pentylether 30 are as follows: a) NiCl.sub.2, NaBH.sub.4, Boc.sub.2O, MeOH, 25 C., 6 h. b) H.sub.2SO.sub.4, MeOH, 65 C., 12 h. c) 1) H.sub.2SO.sub.4, MeOH, 65 C., 12 h; 2) LiOH.Math.H.sub.2O, THF/H.sub.2O, 25 C., 3 h. d) 1) H.sub.2SO.sub.4, MeOH, 65 C., 12 h; 2) LiOH.Math.H.sub.2O, THF/H.sub.2O, 25 C., 3 h; 3) DPPA, Et.sub.3N, toluene, 25-105 C., 6 h, then 1M HCl, 60 C., 12 h.

[0058] The inventors report a storable, thianthrenium-based class of BCP-transfer reagents that can afford potentially valuable small molecules that are in part currently inaccessible by other methods. The inventors anticipate that 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 straightforwardly into small molecules of interest than is possible today.

Materials and Methods

[0059] All reactions were carried out under an ambient atmosphere unless otherwise stated and monitored by thin-layer chromatography (TLC). Air- and moisture-sensitive manipulations were performed using standard Schlenk- and glove-box techniques under an atmosphere of argon or dinitrogen. High-resolution mass spectra were obtained using Q Exactive Plus from Thermo. Concentration under reduced pressure was performed by rotary evaporation at 25-40 C. at an appropriate pressure. Purified compounds were further dried under high vacuum (0.010-0.005 mBar). Yields refer to purified and spectroscopically pure compounds, unless otherwise stated.

Solvents

[0060] Anhydrous DCE and DMA were purchased from Acros Organics and Sigma Aldrich. Other anhydrous solvents were obtained from Phoenix Solvent Drying Systems. All deuterated solvents were purchased from Euriso-Top.

Chromatography

[0061] Thin layer chromatography (TLC) was performed using EMD TLC plates pre-coated with 250 m thickness silica gel 60 F.sub.254 plates and visualized by fluorescence quenching under UV light and KMnO.sub.4 stain. Flash column chromatography was performed using silica gel (40-63 m particle size) purchased from Geduran.

Photochemistry

[0062] All N-alkylation reactions with blue light were carried out using a photoreactor equipped with a blue LED module (KT-Elektronik, 100 W Power LED blau 450 nm Aquarium, 450 nm, 100 W), consisting out of 100 LED-chips. The power of the LED was adjusted using a linear regulator. The vials were cooled with two Peltier-elements (TEC1-12706) while being irradiated with blue light.

Spectroscopy and Instruments

[0063] NMR spectra were recorded on a Bruker Ascend 500 spectrometer operating at 500 MHz, 471 MHz and 126 MHz, for .sup.1H, .sup.19F and .sup.13C acquisitions, respectively; or on a Varian Unity/Inova 600 spectrometer operating at 600 MHz and 151 MHz for .sup.1H and .sup.13C acquisitions, respectively. Chemical shifts are reported in ppm with the solvent residual peak as the internal standard.

Starting Materials

[0064] All substrates were used as received from commercial suppliers, unless otherwise stated. The [1.1.1]propellane solution was prepared according to the literature. Trifluoromethyl thianthrenium triflate salt (CF.sub.3-TT.sup.+ OTf.sup.) was prepared according to the literature. Thianthrene radical cation (TT.sup.+) was prepared according to the literature. Ir(ppy).sub.3 was purchased from Sigma-Aldrich. Ir[(dtbbpy)(ppy).sub.2]PF.sub.6 was purchased from Sigma-Aldrich. CuCl was purchased from Alfa Aesar. Et.sub.3N was purchased from Acros Organics. Ni(dtbbpy)Br.sub.2 was prepared according to the literature. 4CzIPN was prepared according to the literature. The phenols and aryl bromides were prepared according to the literature.

Experimental Part

Preparation of [1.1.1]Propellane Stock Solution

[0065] This compound was prepared following the procedure reported by Anderson:

[0066] To an oven-dried 500 mL round-bottom flask containing a teflon-coated magnetic stirring bar was added 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane (16.0 g, 52.8 mmol, 1.00 equiv.). The flask was sealed with a septum-cap, evacuated, and back-filled with argon three times, and then anhydrous Et.sub.2O (33 mL) was added. The mixture was cooled to 45 C. (dry ice/isopropanol bath). Phenyllithium (56 mL, 1.9 M in Bu.sub.2O, 0.11 mol, 2.0 equiv.) was added dropwise via syringe over 15 min at 45 C. The cooling bath was replaced with an ice bath, and the mixture was warmed to 0 C., and then stirred at this temperature for 2 h.

[0067] Upon completion of the reaction, the mixture was then distilled at 25 C. (70 mbar) using a rotary evaporator with dry ice trap, the receiving flask of which was immersed in a dry ice/acetone bath. The [1.1.1]propellane stock solution (31 mL, 0.85 M in Et.sub.2O, 50%) was transferred to a flame-dried septum-sealed bottle under an inert atmosphere, and stored at 20 C. The approximate concentration of the solution was determined by quantitative .sup.1H NMR spectroscopy with 1,2-dichloroethane as an internal standard.

Quantitative NMR Experiment

[0068] A sample of the solution containing [1.1.1]propellane in diethyl ether (100 L) was diluted with dichloroethane (DCE) (25 L) and CDCl.sub.3 was added (ca. 0.5 mL). The ratio of the DCE:propellane was determined and used for the calculation of the concentration of the propellane solution. This was performed in duplicate and the average of the two runs was used as the final approximated concentration.

Preparation of bicyclo[1.1.1]pentyl thianthrenium salts

Trifluoromethylbicyclo[1.1.1]pentyl thianthrenium salt (3)

##STR00002##

[0069] To a 500 mL round-bottom flask equipped with a stirring bar were added trifluoromethyl thianthrenium salt 1 (9.23 g, 21.2 mmol, 1.00 equiv.) and anhydrous MeCN (152 mL, 0.140 M). The flask was capped with a rubber septum, and subsequently [1.1.1]propellane solution in Et.sub.2O (c=0.85 M, 30 mL, 1.7 g, 1.2 equiv.) was added dropwise via syringe to the reaction over 10 min while stirring. Subsequently, the reaction flask was placed 11 cm away from two Kessil PR160-390 nm LEDs. The mixture was irradiated for 4 h while maintaining the temperature at approximately 35 C. through cooling with a fan. After 4 h, the reaction flask was removed from the two Kessil PR160-390 nm LEDs. The mixture was concentrated under reduced pressure, diluted with DCM (150 mL). The DCM solution was poured into a separation funnel and washed with aqueous NaBF.sub.4 solution (3ca. 150 mL, 10% w/w). All organic phases were combined, dried over MgSO.sub.4 (10 g), filtered, and the solvent evaporated under reduced pressure. The crude material was purified by chromatography on silica gel eluting first with 100% EtOAc and later DCM/i-PrOH (1/0-95/5 (v/v)) to afford the title compound as a brown solid. The solid material was dissolved in DCM (ca. 30 mL), and the flask containing the solid in DCM was placed in an ice bath, at which point the residue was triturated with Et.sub.2O (ca. 200 mL). The flask was kept at 0 C. for 1 h. The resulting solid was decanted and washed with ice-cold Et.sub.2O (2ca. 50 mL), and dried under vacuum overnight yielding a beige solid 3 (6.73 g, 15.3 mmol, 72%).

[00001]$R_f=0.53\left(\mathrm{DCM}/\mathrm{MeOH},10:1\left(v/v\right)\right).$

[0070] Melting point: 150-151 C. (recryst. solvents: DCM/Et.sub.2O (2:1)). The melting process is accompanied by decomposition.

[0071] Elemental analysis calcd (%) for C.sub.18H.sub.14BF.sub.7S.sub.2: C, 49.33, H, 3.22; found: C, 49.09, H, 3.21.

Nonafluorobutyl Thianthrenium Salt (2)

##STR00003##

[0072] Under an ambient atmosphere, a 25 mL two-neck round bottom flask equipped with a teflon-coated magnetic stirring bar, was charged with thianthrene (647 mg, 3.12 mmol, 1.00 equiv.) and DCM (8 mL, c=0.4 M). Subsequently, nonafluorobutanesulfonic anhydride (2.0 g, 1.1 mL, 3.4 mmol, 1.1 equiv.) was added in one portion at 25 C. Upon addition of anhydride, the reaction mixture rapidly turned light purple and gradually deepened, accompanied by formation of suspended particles. The reaction mixture was stirred at 35 C. for 22 h. Subsequently, a saturated aqueous NaHCO.sub.3 solution (ca. 5 mL) was added carefully. At this point, the purple color faded away, and the suspension turned light brown. The suspension was poured into a 50 mL separatory funnel, and the aqueous layer was discarded. The organic layer was concentrated to dryness under reduced pressure, resulting in the formation of a light brown residue. Diethyl ether (10 mL) was added to the residue and the suspension was stirred vigorously at 25 C. for 30 min. The mixture was allowed to stand for 5 min, subsequently, the solvent was decanted carefully. In order to obtain an analytically pure compound, the decanting process was repeated there times with diethyl ether. The resulting yellow slurry was concentrated to dryness under reduced pressure to afford 2 (1.3 g, 1.7 mmol, 55%) as a pale yellow solid.

[00002]$R_f=0.36\left(\mathrm{DCM}/\mathrm{MeOH},10:1\left(v/v\right)\right).$

[0073] Melting point: 125-126 C.

[0074] HRMS-ESI (m/z) calculated for C.sub.16H.sub.8S.sub.2F.sub.9.sup.+ [M-OSO.sub.2C.sub.4F.sub.9].sup.+, 434.9919; found, 434.9918; deviation: 0.3 ppm.

Nonafluorobutylbicyclo[1.1.1] pentyl thianthrenium salt (4)

##STR00004##

[0075] To a 25 mL round-bottom flask equipped with a stirring bar were added nonafluorobutyl thianthrenium salt 2 (734 mg, 1.00 mmol, 1.00 equiv.) and anhydrous MeCN (7.2 mL, 0.14 M). The flask was capped with a rubber septum, and subsequently [1.1.1]propellane solution in Et.sub.2O (c=1.0 M, 1.2 mL, 1.2 equiv.) was added dropwise via syringe to the reaction over 10 min while stirring. Subsequently, the reaction flask was placed in front of two Kessil PR160-390 nm LEDs. The mixture was irradiated for 4 h while maintaining the temperature at approximately 35 C. through cooling with a fan. After 4 h, the reaction flask was removed from the two Kessil PR160-390 nm LEDs. The mixture was concentrated under reduced pressure, diluted with DCM (20 mL). The DCM solution was poured into a separation funnel and washed with aqueous NaBF.sub.4 solution (3ca. 20 mL, 10% w/w). All organic phases were combined, dried over MgSO.sub.4 (10 g), filtered, and the solvent evaporated under reduced pressure. The crude material was purified by chromatography on silica gel eluting first with 100% EtOAc and later DCM/MeOH (100/0-98/2 (v/v)) to afford the title compound 4 as a brown solid (427 mg, 726 mol, 73%).

[00003]$R_f=0.53\left(\mathrm{DCM}/\mathrm{MeOH},10:1\left(v/v\right)\right).$

[0076] Melting point: 112-113 C.

[0077] HRMS-ESI (m/z) calculated for C.sub.21H.sub.14S.sub.2F.sub.9.sup.+ [M-BF.sub.4].sup.+, 501.0390; found, 501.0387; deviation: 0.6 ppm.

Thianthrenium tetrafluoroborate (TT.SUP.+ BF.SUB.4.^.)

##STR00005##

[0078] Thianthrenium tetrafluoroborate was synthesized according to a reported procedure.sup.5. In a nitrogen-filled glove box, thianthrene (2.00 g, 9.25 mmol, 1.00 equiv) was added to nitrosonium tetrafluoroborate (1.13 g, 9.71 mmol, 1.05 equiv) in acetonitrile (80 mL, c=0.12 M) to produce a dark purple solution. The glove box was purged while the reaction mixture was stirred for 1 h at 25 C., at which point, diethyl ether (250 mL) was added to the stirred reaction mixture. The precipitate was collected by filtration and washed with diethyl ether until the filtrate was colorless (510 mL). The filter cake was transferred to a 20 mL borosilicate vial and put under vacuum for 5 h, yielding the title compound as a free-flowing black-purple solid (1.88 g, 6.20 mmol, 67% yield).

[0079] Melting point: 178-179 C. The melting process is accompanied by decomposition.

Determination of Purity:

[0080] A precise amount (approx. 150 mg) of the thianthrenium tetrafluoroborate was dissolved in anhydrous DCM (30 mL) and MeCN (5 mL) under N.sub.2 atmosphere. KI (500 mg, 3.00 mmol) was added, and the mixture was stirred until the deep purple color of TT.sup.+ had been replaced with the dark red brown color of I.sub.2. The liberated iodine was titrated with standard sodium thiosulfate. The procedure was repeated twice, and assays were 99.5% and 98.5% of TT.sup.+ BF.sub.4.sup..

Cyanobicyclo[1.1.1]pentyl thianthrenium salt (5)

##STR00006##

[0081] Under nitrogen atmosphere, to a 4 mL borosilicate vial equipped with a magnetic stir bar were added thianthrenium tetrafluoroborate (TT.sup.+ BF.sub.4.sup.) (120 mg, 0.200 mmol, 2.00 equiv.), CuCN (7.2 mg, 80 moL, 40 mol %), and anhydrous DCM (1.0 mL, c=0.2 M). The vial was sealed with a septum-cap. After cooling to 0 C., TMSCN (50 L, 40 mg, 0.40 mmol, 2.0 equiv.) was added in one portion. The mixture was stirred for 10 min at 0 C. Subsequently, [1.1.1]propellane solution in Et.sub.2O (c=0.90 M) (0.22 mL, 0.20 mmol, 1.0 equiv.) was added to the mixture. Then, the mixture was stirred at 0 C. for 3 h, followed by stirring at 20 C. for 9 h. The mixture was diluted with MeCN (3 mL), and washed with aqueous NaBF.sub.4 solution (13 mL, 10% w/w). The resulting mixture was poured into a separation funnel, vigorously shaken, and the layers were separated. The aqueous layer was extracted with DCM (25 mL). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel eluting with DCM/MeOH (1/0-30/1 (v/v)) to afford the title compound 5 as a pale brown solid (43.4 mg, 0.110 mmol, 55%).

##STR00007##

[0082] Under nitrogen atmosphere, to a 50 mL round-bottom flask equipped with a magnetic stir bar were added thianthrenium tetrafluoroborate (TT.sup.+ BF.sub.4.sup.) (3.18 g, 10.5 mmol, 1.98 equiv.), CuCN (95 mg, 1.1 mmoL, 20 mol %), and anhydrous DCM (26 mL, c=0.20 M). The flask was sealed with a septum-cap. After cooling to 0 C., TMSCN (1.33 mL, 1.05 g, 10.6 mmol, 2.00 equiv.) was added in one portion. The mixture was stirred for 10 min at 0 C. Subsequently, [1.1.1]propellane solution in Et.sub.2O (c=0.71 M) (7.5 mL, 5.3 mmol, 1.0 equiv.) was added to the mixture. Then, the mixture was stirred at 0 C. for 3 h, followed by stirring at 20 C. for 9 h. The mixture was diluted with DCM (20 mL) and MeCN (20 mL), and washed with aqueous NaBF.sub.4 solution (120 mL, 10% w/w). The resulting mixture was poured into a separation funnel, vigorously shaken, and the layers were separated. The aqueous layer was extracted with DCM (250 mL). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The residue was purified by fast chromatography on silica gel eluting with DCM/MeOH (1/0-30/1 (v/v)) to afford the title compound 5 as a pale brown solid (890 mg, 2.25 mmol, 43%).

[00004]$R_f=0.47\left(\mathrm{DCM}/\mathrm{MeOH},10:1\left(v/v\right)\right).$

[0083] Melting point: 147-148 C.

[0084] HRMS-ESI (m/z) calculated for C.sub.18H.sub.14NS.sub.2.sup.+ [M-BF.sub.4].sup.+, 308.0560; found, 308.0562; deviation: +0.8 ppm.

4-Toluenesulfonylbicyclo[1.1.1] pentyl phenoxathiinium salt (8)

##STR00008##

[0085] Under nitrogen atmosphere, to a 25 mL round-bottom flask equipped with a magnetic stir bar were added thiosulfonate 6 (1.5 g, 4.2 mmol, 1.0 equiv.), [1.1.1]propellane solution in Et.sub.2O (c=0.82 M, 5.0 mmol, 6.2 mL, 1.2 equiv.), and CH.sub.3CN (35 mL, c=0.12 M). Subsequently, the reaction flask was placed 5 cm away from two blue LEDs (Kessil A160WE Tuna Blue (460 nm), LED lighting, 40 W). The mixture was irradiated for 12 h while maintaining the temperature at approximately 30 C. through cooling with a fan. The mixture was concentrated under reduced pressure to afford the crude compound 6-1, which was directly used for the next step without further purification.

[0086] To a solution of 6-1 in DCM (14 mL, c=0.30 M) at 0 C. was added 3-chloroperoxybenzoic acid (77%) (0.98 g, 4.4 mmol, 1.0 equiv.). The mixture was stirred for 10 min at 25 C. and then diluted with DCM (10 mL). The suspension was filtered, and the filtrate was washed with saturated Na.sub.2S.sub.2O.sub.3 solution (25 mL) and 1 M NaOH solution (25 mL). The combined organic phase was dried over Na.sub.2SO.sub.4, the resulting suspension was filtered, and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel eluting with EtOAc/pentane (1/10-1/2 (v/v)) to afford the 7 as a colorless solid (1.48 g, 3.37 mmol, 80%).

[00005]$R_f=0.37\left(\mathrm{pentane}/\mathrm{EtOAc},1:1\left(v/v\right)\right).$

[0087] Melting point: 148-149 C.

[0088] HRMS-ESI (m/z) calculated for C.sub.24H.sub.22NaO.sub.4S.sub.2.sup.+ [M+Na].sup.+, 461.0849; found, 461.0852; deviation: +0.7 ppm.

[0089] Under an ambient atmosphere, to a 50 mL round-bottom flask equipped with a magnetic stir bar were added 7 (1.26 g, 2.87 mmol, 1.00 equiv.) and DCM (24 mL, c=0.12 M). The suspension was cooled to 45 C. (dry ice/isopropanol bath), and subsequently trifluoromethanesulfonic anhydride (0.53 mL, 0.93 g, 3.2 mmol, 1.1 equiv.) were added over 1 min. The mixture was stirred at 45 C. for 10 min, and subsequently 50 min at 25 C. The mixture was diluted with DCM (20 mL) and NaBF.sub.4 solution (15 mL, 10% w/w). The mixture was poured into a separation funnel, vigorously shaken, and the layers were separated. The organic phase was washed with aqueous NaBF.sub.4 solution (215 mL, 10% w/w). The aqueous layer was extracted with DCM (150 mL). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The residue was purified by fast chromatography on silica gel eluting with DCM/MeOH (1/0-30/1 (v/v)) to afford 8 as a colorless solid (992 mg, 1.95 mmol, 68%).

[00006]$R_f=0.45\left(\mathrm{DCM}/\mathrm{MeOH},10:1\left(v/v\right)\right).$

[0090] Melting point: 137-138 C.

[0091] HRMS-ESI (m/z) calculated for C.sub.24H.sub.21O.sub.3S.sub.2.sup.+ [M-BF.sub.4].sup.+, 421.0927; found, 421.0927; deviation: +0.0 ppm.

General Procedure for Cu-Catalyzed CO Coupling of 3-5 with Phenols

##STR00009##

[0092] Under nitrogen atmosphere, to a 4 mL borosilicate vial equipped with a magnetic stir bar were added phenol (0.150 mmol, 1.00 equiv.), 3-5 (0.300 mmol, 2.00 equiv.), Ir[(dtbbpy)(ppy).sub.2]PF.sub.6 (3 mg, 3 moL, 2 mol %), CuCl (7.4 mg, 75 moL, 50 mol %), anhydrous DCE (3.0 mL, c=50 mM), and DIPEA (52 L, 39 mg, 0.30 mmol, 2.0 equiv.). The vial was sealed with a septum-cap. Then, the mixture was stirred for 10 min at 25 C., and placed 5 cm away from two blue LEDs (Kessil A160WE Tuna Blue (460 nm), LED lighting, 40 W). The mixture was irradiated for 16 h while maintaining the temperature at approximately 30 C. through cooling with a fan. After irradiation, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the desired product.

General Procedure A for Cu-Catalyzed CN Coupling of 3-5 and 8 with N-Nucleophiles

##STR00010##

[0093] Under air, a 4 mL borosilicate vial equipped with a magnetic stir bar was charged with the N-nucleophile (0.300 mmol, 1.00 equiv.), 3-5 or 8 (1.30-2.00 equiv.), Ir(ppy).sub.3 (4 mg, 6 mol, 2 mol %), and Cu(acac).sub.2 (47 mg, 0.18 mmol, 60 mol %). The vial was sealed with a septum-cap, evacuated, and flushed with argon three times using Schlenk technique. Under positive pressure of argon of 0.1 bars, 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG) (0.18 mL, 0.15 g, 0.90 mmol, 3.0 equiv.) was added, followed by anhydrous MeCN (1.5 mL, c=0.20 M). The mixture was irradiated for 3 h at 10 C. using a photoreactor equipped with a blue LED module (KT-Elektronik, 100 W Power LED blau 450 nm Aquarium, 450 nm, 60 W) (FIG. S8), cooled with two Peltier-elements (TEC1-12706). After irradiation, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the desired product.

General Procedure B for Cu-Catalyzed CN Coupling of 3-5 and 8 with N-Nucleophiles

##STR00011##

[0094] Under air, a 4 mL borosilicate vial equipped with a magnetic stir bar was charged with 3-5 or 8 (0.250 mmol, 1.00 equiv.), the N-nucleophile (1.50-1.80 equiv.), Ir(ppy).sub.3 (3.3 mg, 5.0 mol, 2 mol %), and Cu(acac).sub.2 (39.3 mg, 0.150 mmol, 60 mol %). The vial was sealed with a septum-cap, evacuated, and flushed with argon three times using Schlenk technique. Under positive pressure of argon of 0.1 bars, 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG) (0.15 mL, 0.13 g, 0.75 mmol, 3.0 equiv.) was added, followed by anhydrous MeCN (1.3 mL, c=0.20 M). The mixture was irradiated for 3 h at 10 C. using a photoreactor equipped with a blue LED module (KT-Elektronik, 100 W Power LED blau 450 nm Aquarium, 450 nm, 60 W) (FIG. S8), cooled with two Peltier-elements (TEC1-12706). After irradiation, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the desired product.

General Procedure for Ni-Catalyzed Reductive CC Coupling of 3-5 with Aryl Bromides

##STR00012##

[0095] Under nitrogen atmosphere, to a 4 mL borosilicate vial equipped with a magnetic stir bar were added aryl bromide (0.200 mmol, 1.00 equiv.), 3-5 (0.300 mmol, 1.50 equiv.), 4CzIPN (5 mg, 6 moL, 3 mol %), Ni(dtbbpy)Br.sub.2 (19.4 mg, 40.0 moL, 20.0 mol %), anhydrous DMA (2.0 mL, c=0.10 M), and Et.sub.3N (83 L, 61 mg, 0.60 mmol, 3.0 equiv.). The vial was sealed with a septum-cap. Then, the mixture was stirred for 10 min at 25 C., and placed 5 cm away from two blue LEDs (Kessil A160WE Tuna Blue (460 nm), LED lighting, 40 W). The mixture was irradiated for 16 h while maintaining the temperature at approximately 30 C. through cooling with a fan. After irradiation, EtOAc (6 mL) was added to the mixture, and washed with brine (23 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the desired product.

Bicyclo[1.1.1]pentylether 13

##STR00013##

[0096] Under nitrogen atmosphere, to a 4 mL borosilicate vial equipped with a magnetic stir bar were triclosan (45.2 mg, 0.150 mmol, 1.00 equiv.), 3 (130 mg, 0.300 mmol, 2.00 equiv.), Ir[(dtbbpy)(ppy).sub.2]PF.sub.6 (3 mg, 3 moL, 2 mol %), CuCl (7.4 mg, 75 moL, 50 mol %), anhydrous DCE (3.0 mL, c=50 mM), and DIPEA (52 L, 39 mg, 0.30 mmol, 2.0 equiv.). The vial was sealed with a septum-cap. Then, the mixture was stirred for 10 min at 25 C., and placed 5 cm away from two blue LEDs (Kessil A160WE Tuna Blue, LED lighting, 40 W). The mixture was irradiated for 16 h while maintaining the temperature at approximately 30 C. through cooling with a fan. After irradiation, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with pentane to afford the title compound 13 as a colorless oil (52.9 mg, 0.125 mmol, 83%).

[00007]$R_f=0.5\left(\mathrm{pentanes}/\mathrm{EtOAc},95:5\left(v/v\right)\right).$

[0097] HRMS-EI (m/z) calc'd for C.sub.18H.sub.12O.sub.2F.sub.3Cl.sub.3.sup.+ [M].sup.+, 421.9855; found, 421.9849; deviation: 1.2 ppm.

Bicyclo[1.1.1]pentylether 14

##STR00014##

[0098] Under nitrogen atmosphere, to a 4 mL borosilicate vial equipped with a magnetic stir bar were added 4-bromo phenol (31.1 mg, 0.180 mmol, 1.00 equiv.), 3 (160 mg, 0.360 mmol, 2.00 equiv.), Ir[(dtbbpy)(ppy).sub.2]PF.sub.6 (3 mg, 3 moL, 2 mol %), CuCl (8.9 mg, 90 moL, 50 mol %), anhydrous DCE (3.0 mL, c=60 mM), and DIPEA (63 L, 47 mg, 0.36 mmol, 2.0 equiv.). The vial was sealed with a septum-cap. Then, the mixture was stirred for 10 min at 25 C., and placed 5 cm away from two blue LEDs (Kessil A160WE Tuna Blue, LED lighting, 40 W). The mixture was irradiated for 16 h while maintaining the temperature at approximately 30 C. through cooling with a fan. After irradiation, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with EtOAc/pentane (0:100-1:50 (v/v)) to afford the title compound 14 as a yellow oil (39.2 mg, 0.128 mmol, 71%).

[00008]$R_f=0.5\left(\mathrm{pentane}/\mathrm{EtOAc},20:1\left(v/v\right)\right).$

[0099] HRMS-CI (m/z) calc'd for C.sub.12H.sub.11OF.sub.3Br.sup.+ [M+H].sup.+, 306.9939; found, 306.9940; deviation: +0.4 ppm.

Bicyclo[1.1.1]pentylether 18

##STR00015##

[0100] Under nitrogen atmosphere, to a 4 mL borosilicate vial equipped with a magnetic stir bar were added sinomenine (32.9 mg, 0.100 mmol, 1.00 equiv.), 3 (130 mg, 0.300 mmol, 3.00 equiv.), Ir[(dtbbpy)(ppy).sub.2]PF.sub.6 (2 mg, 2 moL, 2 mol %), CuCl (9.9 mg, 0.10 mmoL, 1.0 equiv), anhydrous DCE (2.0 mL, c=50 mM), and DIPEA (35 L, 26 mg, 0.20 mmol, 2.0 equiv.). The vial was sealed with a septum-cap. Then, the mixture was stirred for 10 min at 25 C., and placed 5 cm away from two blue LEDs (Kessil A160WE Tuna Blue, LED lighting, 40 W). The mixture was irradiated for 16 h while maintaining the temperature at approximately 30 C. through cooling with a fan. After irradiation, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with MeOH/DCM (0:100-1:20 (v/v)) to afford the title compound 18 as a yellow oil (19.0 mg, 41.0 mol, 41%).

[00009]$R_f=0.3\left(\mathrm{MeOH}/\mathrm{DCM},1:10\left(v/v\right)\right).$${\left[\right]}_D^{25}=-52.9\left(c=0.14,{\mathrm{CHCl}}_3\right).$

[0101] HRMS-ESI (m/z) calc'd for C.sub.25H.sub.29NO.sub.4F.sub.3.sup.+ [M+H].sup.+, 464.2043; found, 464.2046; deviation: +0.6 ppm.

Bicyclo[1.1.1]pentylether 32

##STR00016##

[0102] Under nitrogen atmosphere, to a 4 mL borosilicate vial equipped with a magnetic stir bar were added S10 (18.9 mg, 0.100 mmol, 1.00 equiv.), 5 (79.0 mg, 0.200 mmol, 2.00 equiv.), Ir[(dtbbpy)(ppy).sub.2]PF.sub.6 (2 mg, 2 moL, 2 mol %), CuCl (4.9 mg, 50 moL, 50 mol %), anhydrous DCM (2.0 mL, c=0.05 M), and DIPEA (35 L, 26 mg, 0.20 mmol, 2.0 equiv.). The vial was sealed with a septum-cap. Then, the mixture was stirred for 10 min at 25 C., and placed 5 cm away from two blue LEDs (Kessil A160WE Tuna Blue, LED lighting, 40 W). The mixture was irradiated for 16 h while maintaining the temperature at approximately 30 C. through cooling with a fan. After irradiation, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with EtOAc/pentane (0:100-1:8 (v/v)) to afford the title compound 32 as a colorless oil (24.0 mg, 86.0 mol, 86%).

[00010]$R_f=0.5\left(\mathrm{pentane}/\mathrm{EtOAc},3:1\left(v/v\right)\right).$

[0103] HRMS-EI (m/z) calc'd for C.sub.17H.sub.13N.sub.2OF.sup.+ [M].sup.+, 280.1007; found, 280.1006; deviation: +0.1 ppm.

Bicyclo[1.1.1]pentylamine 49

##STR00017##

[0104] A 4 mL borosilicate vial equipped with a magnetic stir bar was charged with ethyl-5-amino-1-(4-methylphenyl)-1H-pyrazol-4-carboxylate (40.0 mg, 0.163 mmol, 1.00 equiv.), 3 (92.9 mg, 0.212 mmol, 1.30 equiv.), Ir(ppy).sub.3 (2.1 mg, 3.3 mol, 2.0 mol %), and Cu(acac).sub.2 (25.6 mg, 98.0 mol, 0.600 equiv.). The vial was sealed with a septum-cap, evacuated, and flushed with argon three times using Schlenk technique. Under positive pressure of argon, anhydrous MeCN (1.0 mL, c=0.20 M) was added, followed by 2-tert-butyl-1,1,3,3-tetramethylguanidine (0.10 mL, 84 mg, 0.49 mmol, 3.0 equiv.) while stirring. The mixture was irradiated for 3 h at 10 C. using a photoreactor equipped with a blue LED module (KT-Elektronik, 100 W Power LED blau 450 nm Aquarium, 450 nm, 60 W), cooled with two Peltier-elements (TEC1-12706). Then, the mixture was concentrated to dryness. The residue was purified by chromatography on silica gel eluting with hexanes/EtOAc (1/0-1/4 (v/v)) to afford the title compound 49 as a light yellow oil (51.0 mg, 0.134 mmol, 82%). R.sub.f=0.80 (EtOAc/hexanes, 1:1 (v/v)).

[0105] HRMS-ESI (m/z) calculated for C.sub.19H.sub.21N.sub.3F.sub.3O.sub.2.sup.+ [M+H].sup.+, 380.1579; found, 380.1580; deviation: +0.2 ppm.

Bicyclo[1.1.1]pentylamine 50

##STR00018##

[0106] A 4 mL borosilicate vial equipped with a magnetic stir bar was charged with cilostazol (0.11 g, 0.30 mmol, 1.0 equiv.), 3 (0.20 g, 4.5 mmol, 1.5 equiv.), Ir(ppy).sub.3 (4 mg, 6 mol, 2 mol %), and Cu(acac).sub.2 (47 mg, 0.18 mmol, 0.60 equiv.). The vial was sealed with a septum-cap, evacuated, and flushed with argon three times using Schlenk technique. Under positive pressure of argon, anhydrous MeCN (1.5 mL, c=0.20 M) was added, followed by 2-tert-butyl-1,1,3,3-tetramethylguanidine (0.19 mL, 0.16 g, 0.94 mmol, 3.1 equiv.) while stirring. The mixture was irradiated for 3 h at 10 C. using a photoreactor equipped with a blue LED module (KT-Elektronik, 100 W Power LED blau 450 nm Aquarium, 450 nm, 60 W), cooled with two Peltier-elements (TEC1-12706). Then, the mixture was concentrated to dryness. The residue was purified by chromatography on silica gel eluting with EtOAc/hexanes (3:10-9:20 (v/v)) to afford the title compound 50 as a brown solid (142 mg, 0.281 mmol, 94%).

[00011]$R_f=0.3\left(\mathrm{EtOAc}/\mathrm{hexanes},3:2\left(v/v\right)\right).$

[0107] Melting point: 109-110 C.

[0108] HRMS-ESI (m/z) calculated for C.sub.26H.sub.32N.sub.5O.sub.2F.sub.3Na.sup.+ [M+Na].sup.+, 526.2407; found, 526.2400; deviation: 1.2 ppm.

Bicyclo[1.1.1]pentylamine 59

##STR00019##

[0109] A 4 mL borosilicate vial equipped with a magnetic stir bar was charged with (S)-4-fluoro--methylbenzylamine (40.0 L, 0.300 mmol, 1.00 equiv.), 3 (236 mg, 0.538 mmol, 1.80 equiv.), Ir(ppy).sub.3 (6.0 mg, 9.2 mol, 2.0 mol %), K.sub.2CO.sub.3 (83 mg, 0.60 mol, 2.0 equiv., and Cu(MeCN).sub.4BF.sub.4 (80.5 mg, 0.256 mmol, 0.853 equiv.). The vial was sealed with a septum-cap, evacuated, and flushed with argon three times using Schlenk technique. Under positive pressure of argon, anhydrous MeCN (1.5 mL, c=0.20 M) was added while stirring. The mixture was irradiated for 3 h at 10 C. using a photoreactor equipped with a blue LED module (KT-Elektronik, 100 W Power LED blau 450 nm Aquarium, 450 nm, 60 W), cooled with two Peltier-elements (TEC1-12706). Then, the mixture was concentrated to dryness. The residue was purified by chromatography on silica gel eluting with EtOAc/hexanes (5:100-3:25 (v/v)) to afford the title compound 59 as a yellow oil (42.0 mg, 0.154 mmol, 51%).

[00012]$R_f=0.3\left(\mathrm{EtOAc}/\mathrm{hexanes},1:5\left(v/v\right)\right).$${\left[\right]}_D^{25}=-21.\left(c=1.17,{\mathrm{CHCl}}_3\right).$

[0110] HRMS-EI (m/z) calculated for C.sub.14H.sub.15NF.sub.4.sup.+ [M].sup.+, 273.1135; found, 273.1135; deviation: +0.2 ppm.

Bicyclo[1.1.1]pentylamine 60

##STR00020##

[0111] A 4 mL borosilicate vial equipped with a magnetic stir bar was charged with 3 (131 mg, 0.300 mmol, 1.00 equiv.), tert-butyl 2-(4R-cis)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-acetate (123 mg, 0.450 mmol, 1.50 equiv.), Ir(ppy).sub.3 (10 mg, 15 mol, 5.0 mol %), K.sub.2CO.sub.3 (83 mg, 0.60 mol, 2.0 equiv), and Cu(MeCN).sub.4BF.sub.4 (94 mg, 0.30 mmol, 1.0 equiv.). The vial was sealed with a septum-cap, evacuated, and flushed with argon three times using Schlenk technique. Under positive pressure of argon, anhydrous MeCN (1.5 mL, c=0.20 M) was added while stirring. The mixture was irradiated for 3 h at 10 C. using a photoreactor equipped with a blue LED module (KT-Elektronik, 100 W Power LED blau 450 nm Aquarium, 450 nm, 60 W), cooled with two Peltier-elements (TEC1-12706). Then, the mixture was concentrated to dryness. The residue was purified by chromatography on silica gel eluting with EtOAc/hexanes (10:100-3:25 (v/v)) to afford the title compound 60 as a yellow oil (29 mg, 0.07 mmol, 24%).

[00013]$R_f=0.4\left(\mathrm{EtOAc}/\mathrm{hexanes},1:1\left(v/v\right)\right).$${\left[\right]}_D^{25}=+9.4\left(c=0.68,{\mathrm{CHCl}}_3\right).$

[0112] HRMS-ESI (m/z) calculated for C.sub.20H.sub.33NF.sub.3O.sub.4.sup.+ [M+H].sup.+, 408.2358; found, 408.2356; deviation: 0.3 ppm.

Bicyclo[1.1.1]pentylmetaxalone 61

##STR00021##

[0113] A 4 mL borosilicate vial equipped with a magnetic stir bar was charged with metaxalone (22.1 mg, 0.100 mmol, 1.00 equiv.), 2 (59.3 mg, 0.150 mmol, 1.50 equiv.), Ir(ppy).sub.3 (0.7 mg, 1 mol, 1 mol %), and Cu(acac).sub.2 (15.5 mg, 60.0 mol, 0.60 equiv.). The vial was sealed with a septum-cap, evacuated, and flushed with argon three times using Schlenk technique. Under positive pressure of argon, 2-tert-butyl-1,1,3,3-tetramethylguanidine (61 L, 51 mg, 0.30 mmol, 3.0 equiv.) was added, followed by anhydrous MeCN (0.5 mL, c=0.2 M). The mixture was irradiated for 3 h at 10 C. using a photoreactor equipped with a blue LED module (KT-Elektronik, 100 W Power LED blau 450 nm Aquarium, 450 nm, 60 W), cooled with two Peltier-elements (TEC1-12706). Then, the mixture was concentrated to dryness. The residue was purified by chromatography on silica gel eluting with EtOAc/pentane (1/5-2/1 (v/v)) to afford the title compound xx as a pale yellow oil (27.8 mg, 89.0 mol, 89%).

[00014]$R_f=0.57\left(\mathrm{pentane}/\mathrm{EtOAc},1:1\left(v/v\right)\right).$

[0114] HRMS-EI (m/z) calculated for C.sub.18H.sub.20N.sub.2O.sub.3.sup.+ [M].sup.+, 312.1471; found, 312.1468; deviation: 0.7 ppm.

Bicyclo[1.1.1]pentylazaindole 62

##STR00022##

[0115] A 4 mL borosilicate vial equipped with a magnetic stir bar was charged with 1H-pyrrolo[3,2-b]pyridine (11.8 mg, 0.100 mmol, 1.00 equiv.), 5 (59.3 mg, 0.150 mmol, 1.50 equiv.), Ir(ppy).sub.3 (0.7 mg, 1 mol, 1 mol %), and Cu(acac).sub.2 (15.5 mg, 60.0 mol, 0.60 equiv.). The vial was sealed with a septum-cap, evacuated, and flushed with argon three times using Schlenk technique. Under positive pressure of argon, 2-tert-butyl-1,1,3,3-tetramethylguanidine (61 L, 51 mg, 0.30 mmol, 3.0 equiv.) was added, followed by anhydrous MeCN (0.5 mL, c=0.2 M). The mixture was irradiated for 3 h at 10 C. using a photoreactor equipped with a blue LED module (KT-Elektronik, 100 W Power LED blau 450 nm Aquarium, 450 nm, 60 W), cooled with two Peltier-elements (TEC1-12706). Then, the mixture was concentrated to dryness. The residue was purified by chromatography on silica gel eluting with EtOAc/pentane (0/100-1/1 (v/v)) to afford the title compound 62 as a pale yellow solid (15.0 mg, 71.7 mol, 72%).

[00015]$R_f=0.17\left(\mathrm{pentane}/\mathrm{EtOAc},1:1\left(v/v\right)\right).$

[0116] Melting point: 173-174 C.

[0117] HRMS-EI (m/z) calculated for C.sub.13H.sub.11N.sub.3.sup.+ [M].sup.+, 209.0947; found, 209.0947; deviation: 0.2 ppm.

Bicyclo[1.1.1]pentylmetaxalone 63

##STR00023##

[0118] A 4 mL borosilicate vial equipped with a magnetic stir bar was charged with metaxalone (22.1 mg, 0.100 mmol, 1.00 equiv.), 8 (102 mg, 0.200 mmol, 1.50 equiv.), Ir(ppy).sub.3 (1.4 mg, 2 mol, 2 mol %), and Cu(acac).sub.2 (15.5 mg, 60.0 mol, 0.60 equiv.). The vial was sealed with a septum-cap, evacuated, and flushed with argon three times using Schlenk technique. Under positive pressure of argon, anhydrous MeCN (0.5 mL, c=0.2 M) was added, followed by 2-tert-butyl-1,1,3,3-tetramethylguanidine (61 L, 51 mg, 0.30 mmol, 3.0 equiv.) while stirring. The mixture was irradiated for 3 h at 10 C. using a photoreactor equipped with a blue LED module (KT-Elektronik, 100 W Power LED blau 450 nm Aquarium, 450 nm, 60 W), cooled with two Peltier-elements (TEC1-12706). Then, the mixture was concentrated to dryness. The residue was purified by chromatography on silica gel eluting with EtOAc/pentane (1/5-2/1 (v/v)) to afford the title compound 63 as a pale yellow oil (26.5 mg, 60.0 mol, 60%).

[00016]$R_f=0.37\left(\mathrm{pentane}/\mathrm{EtOAc},1:1\left(v/v\right)\right).$

[0119] HRMS-ESI (m/z) calculated for C.sub.24H.sub.27NNaO.sub.5S.sup.+ [M+Na].sup.+, 464.1505; found, 464.1502; deviation: 0.6 ppm.

Bicyclo[1.1.1]pentylarene 77

##STR00024##

[0120] Under nitrogen atmosphere, to a 4 mL borosilicate vial equipped with a magnetic stir bar were added S76 (38.1 mg, 0.100 mmol, 1.00 equiv.), 5 (59.3 mg, 0.150 mmol, 1.50 equiv.), 4CzIPN (2.5 mg, 3.0 moL, 3 mol %), Ni(dtbbpy)Br.sub.2 (9.7 mg, 20 moL, 20 mol %), anhydrous DMA (1.0 mL, c=0.10 M), and Et.sub.3N (42 L, 30 mg, 0.30 mmol, 3.0 equiv.). The vial was sealed with a septum-cap. Then, the mixture was stirred for 10 min at 25 C., and placed 5 cm away from two blue LEDs (Kessil A160WE Tuna Blue, LED lighting, 40 W). The mixture was irradiated for 16 h while maintaining the temperature at approximately 30 C. through cooling with a fan. After irradiation, EtOAc (6 mL) was added to the mixture, and washed with brine (23 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with EtOAc/pentane (0:100-1:5 (v/v)) to afford the title compound 77 as a colorless solid (20.4 mg, 51.8 mol, 52%).

[00017]$R_f=0.45\left(\mathrm{pentane}/\mathrm{EtOAc},2:1\left(v/v\right)\right).$

[0121] Melting point: 286-287 C.

[0122] HRMS-ESI (m/z) calc'd for C.sub.24H.sub.19N.sub.5ONa.sup.+ [M+Na].sup.+, 416.1480; found, 416.1482; deviation: +0.4 ppm.

Bicyclo[1.1.1]pentylarene 82

##STR00025##

[0123] Under nitrogen atmosphere, to a 4 mL borosilicate vial equipped with a magnetic stir bar were added S82 (89.2 mg, 0.200 mmol, 1.00 equiv.), 3 (130 mg, 0.300 mmol, 1.50 equiv.), 4CzIPN (5 mg, 6 moL, 3 mol %), Ni(dtbbpy)Br.sub.2 (19.4 mg, 40.0 moL, 20.0 mol %), anhydrous DMA (2.0 mL, c=0.10 M), and Et.sub.3N (83 L, 61 mg, 0.60 mmol, 3.0 equiv.). The vial was sealed with a septum-cap. Then, the mixture was stirred for 10 min at 25 C., and placed 5 cm away from two blue LEDs (Kessil A160WE Tuna Blue, LED lighting, 40 W). The mixture was irradiated for 16 h while maintaining the temperature at approximately 30 C. through cooling with a fan. After irradiation, EtOAc (6 mL) was added to the mixture, and washed with brine (23 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with EtOAc/pentane (0:100-1:6 (v/v)) to afford the title compound 82 as a colorless solid (58.2 mg, 0.116 mmol, 58%).

[00018]$R_f=0.54\left(\mathrm{pentane}/\mathrm{EtOAc},3:1\left(v/v\right)\right).$

[0124] Melting point: 120-121 C.

[0125] HRMS-ESI (m/z) calc'd for C.sub.22H.sub.16N.sub.3O.sub.2S.sub.1F.sub.6 [MH].sup., 500.0877; found, 500.0873; deviation: 0.7 ppm.

Bicyclo[1.1.1]pentylarene 87

##STR00026##

[0126] Under nitrogen atmosphere, to a 4 mL borosilicate vial equipped with a magnetic stir bar were added S87 (72.6 mg, 0.200 mmol, 1.00 equiv.), 3 (130 mg, 0.300 mmol, 1.50 equiv.), 4CzIPN (5 mg, 6 moL, 3 mol %), Ni(dtbbpy)Br.sub.2 (19.4 mg, 40.0 moL, 20.0 mol %), anhydrous DMA (2.0 mL, c=0.10 M), and Et.sub.3N (83 L, 61 mg, 0.60 mmol, 3.0 equiv.). The vial was sealed with a septum-cap. Then, the mixture was stirred for 10 min at 25 C., and placed 5 cm away from two blue LEDs (Kessil A160WE Tuna Blue, LED lighting, 40 W). The mixture was irradiated for 16 h while maintaining the temperature at approximately 30 C. through cooling with a fan. After irradiation, EtOAc (6 mL) was added to the mixture, and washed with brine (23 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with DCM/MeOH (100:0-100:1 (v/v)) to afford the title compound 87 as a colorless solid (49.9 mg, 0.119 mmol, 60%).

[00019]$R_f=0.3\left(\mathrm{DCM}/\mathrm{MeOH},25:1\left(v/v\right)\right).$

[0127] Melting point: 262-263 C.

[0128] HRMS-ESI (m/z) calc'd for C.sub.21H.sub.20F.sub.3N.sub.3O.sub.3Na.sup.+ [M+Na].sup.+, 442.1353; found, 442.1349; deviation: 0.9 ppm.

Synthetic transformations of cyanobicyclo[1.1.1]pentylether 30

Bicyclo[1.1.1]pentylalkyl amine 88

##STR00027##

[0129] To a 25 mL round-bottom flask equipped with a magnetic stir bar were added 30 (30.9 mg, 0.100 mmol, 1.00 equiv), NiCl.sub.2 (19.5 mg, 0.150 mmol, 1.50 equiv), Boc.sub.2O (65.4 mg, 0.300 mmol, 3.00 equiv), and MeOH (10 mL, c=10 mM). The mixture was cooled to 0 C., and NaBH.sub.4 (45.4 mg, 1.20 mmol, 12.0 equiv) was then added over 1 min. The mixture was stirred at 25 C. for 6 h. Then, saturated NH.sub.4Cl solution (5 mL) was added to the mixture, which was then extracted with EtOAc (325 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel eluting with EtOAc/pentane (1:50-1:10 (v/v)) to afford the title compound 88 as a colorless oil (28.9 mg, 70.0 mol, 70%).

[00020]$R_f=0.5\left(\mathrm{pentane}/\mathrm{EtOAc},5:1\left(v/v\right)\right).$

[0130] HRMS-ESI m/z calculated for C.sub.24H.sub.28ClNNaO.sub.3.sup.+ [M+Na].sup.+, 436.1650; found, 436.1650; deviation: 0.1 ppm.

Bicyclo[1.1.1]pentylester 89

##STR00028##

[0131] A 4 mL borosilicate vial equipped with a magnetic stir bar was charged with 30 (30.9 mg, 0.100 mmol, 1.00 equiv) and MeOH (800 L, c=0.125 M). The mixture was cooled to 0 C., and concentrated H.sub.2SO.sub.4 (0.35 mL) was then added over 1 min. The mixture was stirred at 65 C. for 12 h. Cold water (5 mL) was added to the mixture, which was then extracted with EtOAc (315 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel eluting with EtOAc/pentane (1:100-1:30 (v/v)) to afford the title compound 89 as a colorless oil (29.1 mg, 85.0 mol, 85%).

[00021]$R_f=0.31\left(\mathrm{pentane}/\mathrm{EtOAc},10:1\left(v/v\right)\right).$

[0132] HRMS-ESI (m/z) calculated for C.sub.20H.sub.19ClNaO.sub.3.sup.+ [M+Na].sup.+, 365.0916; found, 365.0915; deviation: 0.2 ppm.

Bicyclo[1.1.1]pentyl carboxylic acid 90

##STR00029##

[0133] A 4 mL borosilicate vial equipped with a magnetic stir bar was charged with 89 (130 mg, 0.379 mmol, 1.00 equiv.) and THE/H.sub.2O=2.4/1 (640 L, c=0.594 M). The mixture was cooled to 0 C., and LiOH.Math.H.sub.2O (24 mg, 0.57 mmol, 1.5 equiv.) was then added. The resulting reaction mixture was stirred at 25 C. for 3 h. Then, water (5 mL) was added to the mixture, which was then extracted with EtOAc (23 mL). The aqueous layer was acidified to PH=1-2 with 1M HCl solution and extracted with EtOAc (310 mL). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure to afford the title compound 90 as a colorless oil (110 mg, 0.335 mmol, 88%).

[00022]$R_f=0.56\left(\mathrm{pentane}/\mathrm{EtOAc},1:1\left(v/v\right)\right).$

HRMS-EI (m/z) calculated for C.sub.19H.sub.17ClO.sub.3.sup.+ [M].sup.+, 328.0862; found, 328.0861; deviation: 0.4 ppm.

Bicyclo[1.1.1]pentylamine 91

##STR00030##

[0134] Under argon, to a 5 mL round-bottom flask equipped with a magnetic stir bar were added 90 (32.8 mg, 0.100 mmol, 1.00 equiv.) and anhydrous toluene (0.33 mL, c=0.30 M). Then, Et.sub.3N (14 L, 10 mg, 0.10 mmol, 1.0 equiv.) and diphenylphosphorylazide (DPPA) (22 L, 28 mg, 0.10 mmol, 1.0 equiv.) were added at 25 C. The resulting solution was stirred at 25 C. for 3 h and then at 110 C. for 3 h, to form the corresponding isocyanate intermediate. The reaction mixture was then cooled to 60 C., and 1M HCl (0.17 mL) was added. After 12 h, the reaction mixture was cooled to 25 C. and diluted with EtOAc (5 mL). The organic layer was separated and extracted with 1M HCl (35 mL). The combined aqueous extracts were basified to pH=12-13 by adding 1M NaOH and extracted with DCM (310 mL). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The residue was purified by fast chromatography on silica gel eluting with DCM/MeOH/Et.sub.3N (1/0/0.01-50/1/0.5 (v/v)) to afford the title compound 91 as a yellow oil (15.3 mg, 51.0 mol, 51%).

[0135] HRMS-ESI (m/z) calculated for C.sub.18H.sub.19NClO.sup.+ [M+H].sup.+, 300.1151; found, 300.1150; deviation: 0.3 ppm.

[0136] As discussed above, the incorporation of three-dimensional small-ring scaffolds into bioactive molecules can improve their pharmacokinetic profile, including increased metabolic stability and solubility. Therefore, the rigid 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs) have shown promise as linear bioisosteres for para-substituted benzene rings in drug development. Construction of BCPs commonly requires the cumbersome use of a volatile and labile [1.1.1]propellane solution as reagent, and more stable reagents do not show the versatile reactivity of propellane itself. The lack of practical reagents for BCP introduction currently impedes the potential of this promising scaffold for pharmaceutical development. Here, the present inventors report stable thianthrenium-based BCP reagents for practical oxygen-, nitrogen-, and carbon alkylation reactions that expand the bicyclopentylation scope of any other reagent, including [1.1.1]propellane; aryl BCP ethers are characterized as a new structural motif in chemistry.

[0137] The redox and stereoelectronic properties of the thianthrene scaffold are relevant for both the synthesis via strain release as well as the subsequent reactivity of the new reagents. The weak carbon-sulfur bond can undergo selective mesolytic cleavage upon single-electron reduction to produce BCP radicals that engage in transition-metal-mediated bond formations, including alkylation of phenols, N-heterocycles, amines, amides, sulfonamides, anilines, arenes, and heteroarenes, even at a late-stage with a wide variety of functional groups present. Because the versatile BCP thianthrenium reagents can be prepared centrally and are stable to storage and transport in ambient conditions, they display potential for practical applications in pharmaceutical research for exploration of high-value structures that otherwise may not have been accessed.