Substituted cubanes and methods of making the same

Abstract

Described herein are substituted cubased and methods of making substituted cubanes.

Description

SUBSTITUTED CUBANES AND METHODS OF MAKING THE SAMEFIELD OF THE INVENTION

[0001] Described herein are various substituted cubanes and methods of making the same.BACKGROUND

[0002] Cubanes remain less explored in drug discovery despite being a better geometric match to benzene than other benzene bioisosteres such as bicyclo [l.l.l]pentanes (BCPs). Furthermore, all cubanes in drug candidates, like most benzene bioisosteres, are either mono-substituted or bear linear exit vectors 180° apart, acting solely as substitutes for terminal or para-substituted phenyl rings. Disclosed herein are expedient routes to 1,3- and 1,2-disubstituted cubane building blocks and their functionalization using cross coupling reactions, including amination, alkylation, arylation, and trifluoromethylation reactions.SUMMARY OF THE INVENTION

[0003] In one aspect, described herein is a process for the preparation of cubane- 1 ,3 -dicarboxylic acid 4:comprising the steps of:1) an endocyclic photocyclization of dihydropyridazine 1 to form a Boc-protected diazetidine;2) an electrophilic transcarbamation of the Boc-protected diazetidine to form dicarbamic acid, followed by decarboxylation to form compound 9 and oxidation of 9 followed bynitrogen extrusion to form cyclobutadiene;3) a Diels-Alder cycloaddition of cyclobutadiene with 2,5-dibromoquinone to form bisalkene 2:4) a light-mediated internal [2+2] cycloaddition of bisalkene 2 to form diketone 3: 3 or its monohydrate; and5) a Favorskii ring contraction of diketone 3 or its monohydrate.

[0004] In another aspect, a process for the preparation of cubane- 1,3 -dicarboxylic acid: comprises the steps of:1) an endocyclic photocyclization of a protected dihydropyridazine to for a protected diazetidine;2) deprotection and oxidation of the diazetidine to diazine followed by nitrogen extrusion to provide cyclobutadiene;3) a Diels-Alder cycloaddition of the cyclobutadiene with a quinone substituted with at least two leaving groups to form a bisalkene;4) a light-mediated internal [2+2] cycloaddition of the bisalkene to form a cyclic diketone or its monohydrate; and5) a Favorskii ring contraction of the diketone or its monohydrate to provide cubane- 1,3- dicarboxylic acid.

[0005] In some embodiments, the bisalkene is of the formula:wherein X and Y are the leaving groups independently selected form the group consisting of halo / halide, triflate, tosylate, and mesylate. Moreover, in some embodiments, the cyclic diketone is of the formula:wherein X and Y are defined above.

[0006] In another aspect, described herein is a process for the preparation of dialkyl cubane-1,2- dicarboxylates of Formula (I):wherein R1is alkyl; and R2is alkyl; comprising:1) a light-mediated C-H carboxylation / esterification sequence of dialkyl cubane-l,4-dicarboxylates to provide a trialkyl cubane-l,2,4-tricarboxylate of Formula (II):wherein R3is alkyl;2) a regioselective saponification of the sterically exposed alkyl ester of Formula (II) to provide the monoacid of Formula (III): and3) a decarboxylation of the carboxylic acid of the monoacid of Formula (III).

[0007] In yet another aspect, described herein is a compound having the following structure:wherein R1is alkyl; and R2is alkyl.

[0008] In some embodiments, R1is methyl, ethyl, propyl, iso-propyl, w-butyl, zko-butyl, sec-butyl, or t-butyl; and R2is methyl, ethyl, propyl, iso-propyl, w-butyl, iso-butyl, sec-butyl, or / -butyl. In some embodiments, R1is methyl. In some embodiments. R2is t-butyl. In some embodiments, R1is methyl; and R2is i-butyl.

[0009] In some embodiments, the compound has the following structure:

[0010] In another aspect, described herein is a compound having the following structure:wherein,Rlais H, -C(=O)OR1, -R5, or -CH(R6)(R7); Rlbis H, -C( O)OR2, -R5, or -CH(R6)(R7);Rlcis H, -C(=O)OR1, -R5, or -CH(R6)(R7); Rldis H, -C(=O)OR2, -R5, or -CH(R6)(R7); each R1is independently H or alkyl; each R2is independently H or alkyl;R4is a redox-active ester; each R5is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, - alkylene- (substituted or unsubstituted cycloalkyl), - alkylene-(substituted or unsubstituted heterocycloalkyl), - alkylene-(substituted or unsubstituted aryl), or - alkylene-(substituted or unsubstituted heteroaryl); each of R6and R7is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, - alkylene-(substituted or unsubstituted cycloalkyl), - alkylene-(substituted or unsubstituted heterocycloalkyl), - alkylene-(substituted or unsubstituted aryl), or - alkylene-(substituted or unsubstituted heteroaryl); or R6and R7are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl.

[0011] In some embodiments, the compound has the following structure: wherein,R, ais -C(=O)OR1, -R5, or -CH(R6)(R7); Rlbis -C(=O)OR2, -R5, or -CH(R6)(R7);Rlcis -C(=O)OR1, -R5, or -CH(R6)(R7); and Rldis -C(=O)OR2, -R5, or -CH(R6)(R7).

[0012] In some embodiments, R1is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl; R2is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or / -butyl; and R4is a N-hydroxy-phthalimide ester, N-hydroxy-tetrachlorophthalimide ester, thiohydroxamate ester, 1- hydroxy-7-azabenzotriazole (HOAt) ester, hydroxybenzotriazole (HOBt) ester, or iodomesitylene ester.

[0013] In some embodiments, R1is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or / -butyl; R2is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or / -butyl; and R4is -C(=O)-O-N-succinimidyl, -C(=O)-O-N-phthalimidyl,-C(=O)-O-N-tetrachlorophthalimidyl, or -C(=O)-O-N -1,8 -naphthalimidyl .

[0014] In some embodiments, the compound has one of the following structures:

[0015] In some embodiments, the compound has one of the following structures:

[0016] In another aspect, described herein is a process for the cross-coupling reaction of cubanes comprising the use of a suitable photocatalyst, a suitable copper catalyst, and a cubane comprising a carboxylic acid or a redox active ester. In some embodiments, the cross-coupling reaction forms a carbon-nitrogen or carbon-carbon bond with cubane. In some embodiments, the cross-coupling is a decarboxylative functionalization cross-coupling reaction of a cubane comprising a redox active ester or a carboxylic acid. In some embodiments, the cross-coupling reaction comprises decarboxylative amination, decarboxylative alkylation, decarboxylative trifluoromethylation, decarboxylative arylation, or decarboxylative heteroarylation amination of a cubane comprising aredox active ester or a carboxylic acid. In some embodiments, the cross-coupling reaction comprises a substituted or unsubstituted heteroaryl comprising a NH, an amide comprising aNH, a substituted or unsubstituted alkyl halide, a substituted or unsubstituted aryl halide, a substituted or unsubstituted heteroaryl halide, or an electrophilic trifluoromethylation reagent. In some embodiments, the crosscoupling reaction comprises irradiating the cross-coupling reaction at a suitable wavelength.

[0017] In another aspect, described herein is a process for the amination, alkylation, trifluoromethylation, arylation, or hetero ar ylation of a compound of Formula (IV): wherein,R10is a redox-active ester or -C(=O)OH;R11is H or -C(=O)OR1;R12is H or -C(=O)OR1;R15is H or -C(=O)OR1; and each R1is independently C1-C6alkyl, provided at least one of R11, R12, and R15is not H, comprising a copper catalyzed or mediated decarboxylative amination, decarboxylative alkylation, decarboxylative trifluoromethylation, decarboxylative arylation, or decarboxylative heteroarylation amination of the compound of Formula (IV). In some embodiments, the copper catalyzed or mediated decarboxylative amination, decarboxylative alkylation, decarboxylative trifluoromethylation, decarboxylative arylation, or decarboxylative heteroarylation amination comprises a suitable photocatalyst. In some embodiments, the copper catalyzed or mediated decarboxylative amination, decarboxylative alkylation, decarboxylative trifluoromethylation, decarboxylative arylation, or decarboxylative heteroarylation amination comprises irradiating the reaction mixture a suitable wavelength.

[0018] In another aspect, described herein is a process for the amination a compound of Formula (IV) comprising a decarboxylative amination of the compound of Formula (IV), wherein R10is - C(=O)OH. In some embodiments, the decarboxylative amination of the compound of Formula (IV) comprises reacting the compound of Formula (IV) wherein R10is -C(=O)OH with a cyclic or acyclic hypervalent iodine (III) reagent, followed by adding a suitable photocatalyst, a suitable copper catalyst, a suitable base, a suitable solvent, and a substituted or unsubstituted 5-10 memberedheteroaryl comprising a NH or an amide comprising a NH, and irradiating the mixture at a suitable wavelength.

[0019] In another aspect, described herein is a process for the alkylation of a compound of Formula (IV) comprising metallaphotoredox catalysis of a compound of Formula (IV) wherein R10is a redox active ester with a substituted or unsubstituted alkyl halide.

[0020] In some embodiments, the metallaphotoredox catalysis comprises combining a compound of Formula (IV) wherein R10is a redox active ester, a substituted or unsubstituted alkyl halide, a halogen atom abstractor, a suitable photocatalyst, and a suitable copper catalyst, and irradiating the mixture at a suitable wavelength.

[0021] In another aspect, described herein is a process for the trifluoromethylation of a compound of Formula (IV) comprising the oxidative decarboxylation of a compound of Formula (IV) wherein R10is -C(=O)OH in the presence of an electrophilic trifluoromethylation reagent.

[0022] Disclosed herein is a process for the preparation of an aryl-cubane or heteroaryl-cubane comprising metallaphotoredox catalysis of a compound of Formula (IV) wherein R10is a redox active ester with a substituted or unsubstituted aryl halide or substituted or unsubstituted 5heteroaryl halide.

[0023] In some embodiments, the metallaphotoredox catalysis comprises combining a compound of Formula (IV) wherein R10is a redox active ester, a substituted or unsubstituted aryl halide or substituted or unsubstituted heteroaryl halide, a halogen atom abstractor, a suitable photocatalyst, a suitable copper catalyst, and a suitable base, and irradiating the mixture at a suitable wavelength. In some embodiments, the suitable photocatalyst is an organic photocatalyst, an organometallic photocatalyst, or an inorganic photocatalyst. In some embodiments, the organic photocatalyst comprises a substituted or unsubstituted cyanobenzene.

[0024] In another aspect, a method of cubane alkylation or arylation comprises forming a cubyl radical from a cubane redox active ester, and forming an alkyl radical or aryl radical via halogen extraction from an alkyl halide or aryl halode. The cubyl radical is C-C cross coupled with the alkyl radical or the aryl radical with copper catalyst.

[0025] In some embodiments, the cubyl radical is reductively generated via charge transfer from a transition metal catalyst. The transition metal catalyst, in some embodiments, is a photocatalyst.The photocatalyst, in some embodiemnts, can also generate a silyl radical for the halogen extraction from the alkyl halide or the aryl halide.

[0026] In another aspect, described herein is a cubane having the following structure:wherein R1is C1-C6alkyl.

[0027] In some embodiments, described herein are compounds of Formula (III): or a salt thereof,whereinR1is C1-C6alkyl; andR2is C1-C6alkyl.

[0028] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIG. 1 illustrates a mechanistic pathway for cubane alkylation or arylation, according to some embodiments.DETAILED DESCRIPTION OF THE INVENTION

[0030] The replacement of benzene rings with sp3-hybridized bioisosteres in drug candidates generally improves pharmacokinetic properties while retaining biological activity. Rigid, strained frameworks, such as bicyclo [l.l.ljpentane and cubane, are particularly well-suited since the ring strain imparts high bond strength and thus metabolic stability on its C-H bonds. Cubane is an effective bioisostere since it provides the closest geometric match to benzene. At present, however, all cubanes in drug design, like almost all benzene bioisosteres, act solely as substitutes for mono- or pnru-substituted benzene rings. This is due to the difficulty of accessing 1,3- and 1,2-disubstitutedcubane precursors. The adoption of cubane in drug design has been further hindered by the incompatibility of cross-coupling reactions with the cubane scaffold, owing to a competing metal- catalyzed valence isomerization.

[0031] Disclosed herein are expedient routes to 1,3- and 1,2-disubstituted cubane building blocks using a convenient cyclobutadiene precursor and a photolytic C-H carboxylation reaction, respectively. Also disclosed are methods for the functionalization of cubanes, such as C-N, C- C(sp3), C-C(sp2), and C-CF3 cross-coupling protocols, that are made possible by utilizing the slow oxidative addition and rapid reductive elimination of copper. In some embodiments, the methods disclosed herein permit the facile elaboration of all cubane isomers into drug candidates thus enabling advantageous bioisosteric replacement of ortho-, meta-, and para- substituted benzenes.

[0032] Two routes to 1,3-disubstituted cubanes have been reported in the literature, each of which have drawbacks. In 1966, the Pettit group described a 3-step protocol to prepare 1,3-disubstituted cubane that features a Diels- Alder reaction between cyclobutadiene, generated in situ from cyclobutadieneiron tricarbonyl, and 2,5-dibromobenzoquinone (Barborak, J. C, Watts, L. & Pettit, R. A Convenient Synthesis of the Cubane System. J. Am. Chem. Soc. 88, 1328-1329 (1966)).Scheme A. Pettit group 3-step protocol to prepare 1,3-disubstituted cubane

[0033] To date, this Pettit group synthesis has seen no application in medicinal chemistry, likely owing to the arduous synthesis of the cyclobutadiene precursor cyclobutadieneiron tricarbonyl, which involves 4 steps (9% overall yield) and requires inconvenient reagents such as chlorine gas, benzene, and highly toxic diiron nonacarbonyl.

[0034] In 1993, Ueda and co-workers showed that the enones shown in Scheme B could be converted to 1,4-disubstituted cubane and 1,3 -disubstituted cubane (T. Nigo, T. Hasegawa, Y. Kuwatani and I. Ueda, Bull. Chem. Soc. Jpn., 1993, 66, 2068-2072).Scheme B. Ueda and co-workers’ protocol to prepare 1,3-disubstituted cubane

[0035] This route by Ueda and co-workers is not viable for scale-up of 1,3 -disubstituted cubane 4 due to the difficulty in accessing the necessary enone E2 in appreciable quantities, which was obtained in only 4.5% yield as a side product of the synthesis of the regioisomeric enone El.

[0036] Disclosed herein is an improved method for generating cyclobutadiene and its use in the synthesis of dimethyl cubane-l,3-dicarboxylate.Novel synthesis of cyclobutadiene

[0037] The novel route to cyclobutadiene is shown in Scheme 1.Scheme 1. Improved method for in situ generation of cyclobutadiene

[0038] The process commences with light-mediated, endocyclic 4-7r-cyclization of dihydropyridazine 1 to form the Boc-protected diazetidine. Addition of TMSOTf in presence of a lutidine buffer forms a TMS-protected dicarbamate by electrophilic transcarbamation. Then, formation of a highly labile dicarbamic acid is immediately followed by decarboxylation to form the equally labile free diazetidine 5, which is oxidized by the dibromobenzoquinone to form diazine 6. Extrusion of N2 then acts as a driving force for the formation of cyclobutadiene.

[0039] Finally, the antiaromatic cyclobutadiene is highly activated to undergo an e / Wo-selective Diels- Alder reaction with an electron-poor alkene such as benzoquinone to form bisalkene 2. As a key design principle, the cyclobutadiene is generated in an oxidative pathway rather than under reducing conditions, thus enabling it to be generated in presence of a benzoquinone, which is an oxidant.

[0040] Excess dibromobenzoquinone is removed from bisalkene 2 by using a reductive workup with activated charcoal to prevent decomposition by sensitization. Bisalkene 2 can be used in the next step with no purification. As shown in Scheme 2, crude bisalkene 2 undergoes a subsequent internal [2+2] light-mediated cycloaddition to afford diketone 3 or its monohydrate.Scheme 2. Internal [2+2] cycloaddition towards diketone 3

[0041] Favorskii ring contraction and esterification then provides dimethyl cubane-1,3- dicarboxylate 4.

[0042] First, Favorskii ring contraction of diketone 3 or its monohydrate provides cubane-1,3- dicarboxylic acid 4 as shown in Scheme 3.Scheme 3. Favorskii Ring Contraction

[0043] In some embodiments, cubane- 1,3 -dicarboxylic acid 4 can be purified before esterification.In some embodiments, crude cubane-l,3-dicarboxylic acid 4 can be alkylated as shown in Scheme 4.Scheme 4. Esterification of cubane-l,3-dicarboxylic acid

[0044] Alkylation of cubane-l,3-dicarboxylic acid 4 with an alkyl halide in the presence of a suitable base in a suitable solvent yields dialkyl cubane-l,3-dicarboxylate 4a. In some embodiments, the suitable base is Li2CO3, Na2CO3, K2CO3, Cs2CO3, NaH, NaOAc, KOAc, or the like, hi someembodiments, the suitable base is CS2CO3. In some embodiments, the suitable solvent used in the alkylation step is acetonitrile, dimethylformamide, dimethylacetamide, dimethoxyethane, 2- methyltetrahydrofuran, methyl tert-butyl ether, tetrahydrofuran, diisopropyl ether, 1,4-dioxane, dimethyl sulfoxide, or a combination thereof. In some embodiments, the suitable solvent used in the alkylation step is dimethylformamide. In some embodiments, the alkyl halide is methyl iodide, methyl bromide, ethyl iodide, or ethyl bromide. In some embodiments, the alkyl halide is methyl iodide. In some embodiments, the reaction is performed at room temperature. In some embodiments, the reaction is performed at a temperature above room temperature. In some embodiments, the reaction is performed at about 40 °C.

[0045] Alternative reactions for the conversion of carboxylic acids to esters include Fischer esterification, conversion of the carboxylic acid(s) to acyl chlorides, and reaction with alcohols or alkoxides. In some embodiments, Fischer esterification is performed in a suitable alcohol solvent in the presence of a suitable acid. In some embodiments, the suitable alcohol solvent is methanol, ethanol, or isopropanol. In some embodiments, the suitable acid is an inorganic acid. In some embodiments, the suitable acid is HC1, HBr, HNO3, H2SO4, or the like. In some embodiments, the reaction is performed at an elevated temperature. In some embodiments, conversion of the carboxylic acid(s) to acyl chlorides includes treating the carboxylic acid(s) with phosphorus(V) chloride (PCI5), phosphorus(III) chloride (PCI3), thionyl chloride, or oxalyl chloride.Synthesis of l-terributyl-2-methyl cubane-l,2-dicarboxylate

[0046] The cubane-l,2-diester 11 can be accessed as shown in Scheme 5.Scheme 5. Synthesis of Cubane-l,2-diester 11.

[0047] Starting with the symmetrical, commercially available dimethyl cubane-l,4-dicarboxylate8, a light-mediated one-pot C-H carboxylation / esterification sequence can provide cubane triester 9.Deprotection of the sterically exposed methyl ester of 9 can give the monoacid 10. Photoredox- mediated decarboxylation of cubane SI in the presence of 1,4-cyclohexadiene can provid cubane- 1,2-diester 11.

[0048] The light-mediated one-pot C-H carboxylation / esterification sequence can begin with adding oxalyl chloride to dimethyl cubane- 1,4-dicarboxylate 8 in acetonitrile and irradiating the reaction at a suitable wavelength. In some embodiments, the photoreaction is carried out for about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, or more than 4 hours. Pyridine and tBuOH can then be added and the reaction can be carried out for, e.g., about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, 11 hours, about 11.5 hours, about 12 hours, about 12.5 hours, about 13 hours, about 14.5 hours, about 15 hours, about 15.5 hours, about 16 hours, about 16.5 hours, about 17 hours, about 18.5 hours, about 19 hours, or more than 20 hours. In some embodiments, the suitable wavelength is about 380 nm to about 700 nm, about 100 nm to about 280 nm, about 280 nm to about 315 nm, about 315 nm to about 400 nm, about 400 nm to about 440 nm, about 420 nm to about 460 nm, about 400 nm to about 500 nm, about 280 nm to about 600 nm, about 280 nm, about 300 nm, about 320 nm, about 340 nm, about 360 nm, about 380 nm, about 400 nm, about 420 nm, about 440 nm, about 480 nm, about 500 nm, about 520 nm, about 540 nm, about 560 nm, about 580 nm, or about 600 nm. In some embodiments, the suitable wavelength is generated by a light-emitting diode (LED).

[0049] Regioselective saponification of cubane triester 9 followed by acid neutralization can afford the monoacid 10. In some embodiments, cubane triester 9 is treated with sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, potassium phosphate or lithium hydroxide in a suitable solvent. In some embodiments, the suitable solvent is water, methanol, ethanol, tetrahydrofuran, ethyl acetate, dimethylformamide, or a combination thereof. In some embodiments, the saponification is performed with sodium hydroxide in a mixture of tetrahydrofuran and methanol. In some embodiments, acid neutralization is performed with acetic acid, citric acid, oxalic acid, lactic acid, hydrochloric acid, sulfuric acid, or potassium hydrogen sulfate. In some embodiments, acid neutralization is performed with potassium hydrogen sulfate.

[0050] The monoacid 10 can be coupled with N-hydroxyphthalimide in the presence of a coupling reagent in a suitable solvent to provide the redox-active ester SI. In some embodiments, the coupling reagent is N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC), l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDAC), N,N'-dicyclohexylcarbodiimide (DCC), N,N'- diisopropylcarbodiimide (DIC), 1, 3 -diisopropylcarbodiimide, N,N'-diisopropylcarbodiimide, 1,3-diisopropylcarbodiimide, l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate (HATU), l,l'-carbonyldiimidazole (GDI), 1 -Hydroxybenzotriazole (HOBt), benzotriazol- l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), fluoro- N,N,N',N'-bis(tetramethylene)formamidinium hexafluorophosphate (BTFFH), chloro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate, fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH), or the like. In some embodiments, the suitable solvent is dichloromethane, dimethylformamide, or tetrahydrofuran. In some embodiments, the monoacid 10 can be coupled with Ar-hydroxyphthalimide in the presence of EDC, dimethylaminopyridine (DMAP), and in dichloromethane.

[0051] Additional suitable coupling conditions include the use of EDC, DMAP, and tetrahydrofuran at room temperature. In some embodiments, the suitable coupling conditions include the use of HATU, triethylamine and dichloromethane or dimethylformamide at room temperature. In some embodiments, the suitable coupling conditions include the use of GDI, tetrahydrofuran and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature. Additional bases used for such coupling reactions include triethylamine, diisopropylethylamine, and the like.

[0052] Photoredox-mediated decarboxylation of the redox-active ester SI can be performed with a suitable photocatalyst in the presence of a suitable hydrogen atom donor at a suitable wavelength to provide l-tert-butyl-2-methyl cubane-l,2-dicarboxylate 11. In some embodiments, the suitable photocatalyst is an organic photocatalyst or inorganic photocatalyst. In some embodiments, the suitable photocatalyst is an iridium photocatalyst. In some embodiments, the suitable photocatalyst is a ruthenium photocatalyst. In some embodiments, the suitable photocatalyst is a copper photocatalyst. In some embodiments, the suitable photocatalyst is an organic photocatalyst. In some embodiments, the suitable photocatalyst is an organic photocatalyst comprising a substituted orembodiments, the suitable hydrogen atom donor is 1,4-cyclohexadiene. In some embodiments, the suitable wavelength is about 380 nm to about 700 nm, about 100 nm to about 280 nm, about 280 nm to about 315 nm, about 315 nm to about 400 nm, about 400 nm to about 440 nm, about 420 nm to about 460 nm, about 400 nm to about 500 nm, about 280 nm to about 600 nm, about 280 nm, about 300 nm, about 320 nm, about 340 nm, about 360 nm, about 380 nm, about 400 nm, about 420 nm, about 440 nm, about 480 nm, about 500 nm, about 520 nm, about 540 nm, about 560 nm, about 580 nm, or about 600 nm. In some embodiments, the suitable wavelength is generated by a light-emitting diode (LED). In some embodiments, the photoredox-mediated decarboxylation is performed with [Ir(ppy)2(dtbbpy)]PFe, triethylamine, and 1,4-cyclohexadiene in dimethylacetamide (DMA) inside a photoreactor at 450 nm to provide l-tert-butyl-2 -methyl cubane- 1,2-dicarboxylate 11.Copper-mediated cross-coupling protocols

[0053] Disclosed herein is a general and modular metal cross-coupling platform that is compatible with the highly strained cubane framework and uses the cubane diesters described herein. Typical cross-coupling catalysts, such as nickel and palladium complexes, are known to facilitate cubane decomposition by strain-releasing valence bond isomerization to generate products such as cuneane and cyclooctatetraene.

[0054] Undesirable pathways, including oxidative insertion into the cubane framework and decomposition of metal-cubane complexes, can be suppressed under a copper catalytic manifold because copper is known to undergo slow oxidative addition and rapid reductive elimination. The former property prevents it from decomposing cubane via oxidative insertion while the latter ensures that reductive elimination outcompetes valence isomerization.

[0055] To circumvent the shortcomings of traditional metal cross coupling reactions, metallaphotoredox catalysis (i.e., merger of photoredox and transition metal catalysis) was used. In embodiments, the combination of copper and photoredox catalysis enabled C(sp3)-C(sp2) andC(sp3)-C(sp3) bond formation using cubane carboxylic acids (via decarboxylation) as coupling partners.

[0056] In some embodiments, decarboxylative cross-coupling (e.g., decarboxylative arylation, decarboxylative heteroarylation, decarboxylative alkylation, decarboxylative fluoroalkylation, decarboxylative amination, and the like) using redox-active esters of cubane carboxylic acids were used to functionalize cubanes. Redox-active esters, such as N-hydroxy-phthalimide esters, thiohydroxamate esters (also known as Barton esters), in-situ esters derived from l-hydroxy-7- azabenzotriazole (HO At), in-situ esters derived from hydroxybenzotriazole (HOBt), and iodomesitylene dicarboxylates, are particularly suitable substrates in decarboxylative crosscouplings involving esters. Methods of making such esters, for example, from their corresponding carboxylic acids, are well-known in the art and described herein.

[0057] In another aspect, described herein is a compound having the following structure:wherein,or R6and R7are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted Cs-Ciocycloalkyl or substituted or unsubstituted 3-10 membered heterocycloalkyl.

[0058] In some embodiments, the compound has the following structure: wherein,Rlais -C(=O)OR1, -R5, or -CH(R6)(R7); Rlbis -C(=O)OR2, -R5, or -CH(R6)(R7); Rlcis -C(=O)OR1, -R5, or -CH(R6)(R7); and Rldis -C(=O)OR2, -R5, or -CH(R6)(R7).

[0059] In some embodiments, Rlais -C(=O)OR1. In some embodiments, Rlais -R5or -CH(R6)(R7). In some embodiments, Rlais -R5. In some embodiments, Rlais -CH(R6)(R7).

[0060] In some embodiments, Rlbis -C(=O)OR2. In some embodiments, Rlbis -R5or -CH(R6)(R7). In some embodiments, Rlbis -R5. In some embodiments, Rlbis -CH(R6)(R7).

[0061] In some embodiments, Rlcis -C(=O)OR1. In some embodiments, Rlcis -R5or -CH(R6)(R7). In some embodiments, Rlcis -R5. In some embodiments, Rlcis -CH(R6)(R7).

[0062] In some embodiments, Rldis -C(=O)OR2. In some embodiments, Rldis -R5or -CH(R6)(R7). In some embodiments, Rldis -R5. In some embodiments, Rldis -CH(R6)(R7).

[0063] In some embodiments, each R5is independently substituted or unsubstituted C1-C6alkyl, -embodiments, each R5is independently -C1-C6alkylene-(substituted or unsubstituted C3-Ciocycloalkyl). In some embodiments, each R5is independently -C1-C6alkylene-(substituted or unsubstituted 3-10 membered heterocycloalkyl). In some embodiments, each R5is independentlyindependently C1-C6alkylene-(substituted or unsubstituted 5-10 membered heteroaryl).

[0064] In some embodiments, each of R6and R7is independently substituted or unsubstituted C1-Cioaryl), or -C1-C6alkylene-(substituted or unsubstituted 5-10 membered heteroaryl).

[0065] In some embodiments, each of R6and R7is independently substituted or unsubstituted C1-membered heteroaryl).

[0066] In some embodiments,hydroxy-7-azabenzotriazole (HO At) ester, hydroxybenzotriazole (HOBt) ester, or iodomesitylene ester.

[0067] In some embodiments, R1is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl; R2is methyl, ethyl, propyl, iso-propyl, H-butyl, iso-butyl, sec-butyl, or t-butyl; and R4is -C(=O)-O-N-succinimidyl, -C(=O)-O-N-phthalimidyl,-C(=O)-O-N-tetrachlorophthalimidyl, or -C(=O)-O-N- 1 ,8-naphthalimidyl.

[0068] In some embodiments, the compound has one of the following structures:

[0069] In some embodiments, the compound has one of the following structures:

[0070] Suitable copper catalysts include copper(II) acetylacetonate, copper(II) tertbutylacetoacetate, copper(II) ethylaceto acetate, copper(II) trifluoromethanesulfonate, copper(II) oxide, copper(II) bromide, copper(II) chloride, copper(II) sulfate, copper(II) acetate, bis(ethylenediamine)copper(II) hydroxide, copper(II) nitrate hemi(pentahydrate), copper(II) tartrate, and dichloro(l , 10-phenanthroline)copper(II).

[0071] In some embodiments, the copper catalyst used is Cu(acac)2,Amination of Cubanes

[0072] An array of N-nucleophiles, including N -heterocycles, and amides, can be used in C-N coupling to provide N-cubane products as show in Scheme 7.Scheme 7. Copper-mediated amination of cubanes162

[0073] The process for the amination of cubanes comprises a decarboxylative amination of a cubane-carboxylic acid.

[0074] In some embodiments, the decarboxylative amination of the cubane-carboxylic acid comprises reacting the cubane-carboxylic acid with a hypervalent iodine (III) reagent, followed by the addition of a suitable photocatalyst, a suitable copper catalyst, a suitable base, a suitable solvent, and a substituted or unsubstituted 5-10 membered heteroaryl comprising a NH or an amide comprising a NH, and irradiating the mixture at a suitable wavelength.

[0075] In some embodiments, the hypervalent iodine (III) reagent is benziodoxole (Bl)-alkoxyl (BIOR), benziodoxole (Bl)-hydroxyl (BIOH), benziodoxole (Bl)-acetate (BIOAc), or iodomesitylene diacetate (MesI(Oac)2). In some embodiments, the hypervalent iodine (III) reagent is a cyclic hypervalent iodine (III) reagent. In some embodiments, the hypervalent iodine (III) reagent is an acyclic hypervalent iodine (III) reagent. In some embodiments, the hypervalent iodine (III) reagent is of the formula (ArI(Oac)2), wherein Ar is a substituted or unsubstituted phenyl ring. In some embodiments, the hypervalent iodine (III) reagent is of the formula (ArI(Oac)2), wherein Ar is a substituted or unsubstituted phenyl ring, wherein each substituent is independently -Me, -Et, phenyl, -F, -Cl, -Ome, -OCO2Me, -OCO2Et, or -OCF3. In some embodiments, the hypervalent iodine (III) reagent is of the formula (HarI(Oac)2), wherein HAr is a substituted or unsubstituted 5- or 6- membered heteroatomic ring. In some embodiments, the hypervalent iodine (III) reagent is of the formula (HArI(OAc)2), wherein HAr is a substituted or unsubstituted 5- or 6- membered heteroatomic ring, wherein each substituent is independently -Me, -Et, phenyl, -F, -Cl, -OMe, -OCO2Me, -OCO2Et, or -OCF3.

[0076] In some embodiments, the cubane carboxylic acid, such as 4-(methoxycarbonyl)cubane-l- carboxylic acid 16, can be treated with iodomesitylene diacetate (MesI(OAc)2) in a suitable solvent, such as toluene, to form iodomesityl ene bis(4-(methoxycarbonyl)cubane- 1 -carboxylate). In someembodiments, iodomesitylene bis(4-(methoxycarbonyl)cubane-l -carboxylate) can be purified. In some embodiments, iodomesityl ene bis(4-(methoxycarbonyl)cubane-l -carboxylate) is used directly in amination reactions after removal of the suitable solvent. In some embodiments, the decarboxylative amination of the cubane-carboxylic acid comprises reacting the cubane-carboxylic acid with a hypervalent iodine (III) reagent in a suitable solvent. In some embodiments, the decarboxylative amination of the cubane-carboxylic acid comprises reacting the cubane-carboxylic acid with a hypervalent iodine (III) reagent in a suitable solvent to afford a cubanyl ester with a O-I bond. In some embodiments, the suitable solvent is toluene, benzene, xylenes, u,a,a-trifluorotoluene, chlorobenzene, chloroform, 1,2-dichloroethane, 1,4-dioxane, or methyl tert-butyl ether. In some embodiments, the suitable solvent is toluene, benzene, xylenes, or chlorobenzene. In some embodiments, the suitable solvent is toluene, benzene, or chlorobenzene. In some embodiments, the suitable solvent is toluene or benzene. In some embodiments, the suitable solvent is toluene.

[0077] In some embodiments, the suitable photocatalyst is an organic photocatalyst or inorganic photocatalyst. In some embodiments, the suitable photocatalyst is an iridium photocatalyst. In some embodiments, the suitable photocatalyst is a ruthenium photocatalyst. In some embodiments, the suitable photocatalyst is a copper photocatalyst. In some embodiments, the suitable photocatalyst is an organic photocatalyst. In some embodiments, the suitable photocatalyst is an organic photocatalyst comprising a substituted or unsubstituted cyanobenzene. In some embodiments, the suitable photocatalyst is Eosin Y, 1 ,2,3,5- tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4-CzIPN), 2,4,5,6-tetrakis(9H-carbazol-9-yl) isophthalonitrile, Ir(dF(CF3))2(dtbbpy)PF6, Ir(ppy)g, Ir(dFppy)3, Ir(ppy)2(dOMebpy)PF6, Ir(ppy)2(dtbbpy)PF6, Ir(ppy)2(bpy)PFe, Ir(FMeppy)2(dtbbpy)PF6, Ir(dFMeppy)2(dtbbpy)PF 6, Ir(dFMeppy)2(bpy)PF 6, Ir(dF (F)ppy)2(dtbbpy)PF 6, Ir(dF(CF3)ppy)2(bpy)PF6, Ir(dF(CF3)ppy)2(4,4’-dFbpy)PF6, Ir(dF(CF3)ppy)2(5,5’-dFbpy)PF6, Ru(bpy)3Ch, or [Ru(4,4’-d(Cl)(bpy)3](PF6)2. In some embodiments, the suitable photocatalyst is l,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4-CzIPN) or 2,4,5,6-tetrakis(9H-carbazol-9-yl) isophthalonitrile. In some embodiments, the suitable photocatalyst is Ir(dF(CF3))2(dtbbpy)PF6, Ir(ppy)3, Ir(dFppy)s, Ir(ppy)2(dOMebpy)PFe, Ir(ppy)2(dtbbpy)PF6, Ir(ppy)2(bpy)PFe, Ir(FMeppy)2(dtbbpy)PF6, Ir(dFMeppy)2(dtbbpy)PF6, Ir(dFMeppy)2(bpy)PF6, Ir(dF(F)ppy)2(dtbbpy)PF6, Ir(dF(CF3)ppy)2(bpy)PF6, Ir(dF(CF3)ppy)2(4,4’-dFbpy)PF6, or Ir(dF(CF3)ppy)2(5,5’-dFbpy)PF6. In some embodiments, the suitable photocatalyst is Ru(bpy)3Ch or [Ru(4,4’-d(Cl)(bpy)3](PF6)2.

[0078] In some embodiments, the suitable copper catalyst is a copper (I) catalyst or copper (II) catalyst. In some embodiments, the copper catalyst used is Cu(acac)2,

[0079] In some embodiments, the suitable base is an organic base or inorganic base. In some embodiments, the suitable base is triethylamine, diisopropylethylamine, sec-butylamine, 1 ,2, 2,6,6- pentamethylpiperidine, tributylamine, or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0080] In some embodiments, the suitable solvent is 1,4-dioxane, acetone, dimethylsulfoxide, N,N- dimethylacetamide, dimethylformamide, or acetonitrile. In some embodiments, the suitable solvent is 1,4-dioxane, acetone, acetonitrile. In some embodiments, the suitable solvent is 1,4-dioxane.

[0081] In some embodiments, the suitable wavelength is about 380 run to about 700 nm, about 100 nm to about 280 nm, about 280 nm to about 315 nm, about 315 nm to about 400 nm, about 400 nm to about 440 nm, about 420 nm to about 460 nm, or about 400 nm to about 500 nm.

[0082] In some embodiments, the suitable wavelength is about 280 nm to about 600 nm, about 280 nm, about 300 nm, about 320 nm, about 340 nm, about 360 nm, about 380 nm, about 400 nm, about 420 nm, about 440 nm, about 480 nm, about 500 nm, about 520 nm, about 540 nm, about 560 nm, about 580 nm, or about 600 nm. In some embodiments, the suitable wavelength is generated by a light-emitting diode (LED). In some embodiments, the suitable wavelength is generated by an integrated photoreactor.

[0083] Examples of heteroaromatic amines compatible with these reaction conditions include, but are not limited to, substituted or unsubstituted imidazoles, substituted or unsubstituted pyrazoles, substituted or unsubstituted triazoles, substituted or unsubstituted tetrazoles, substituted or unsubstituted pyrroles, substituted or unsubstituted indoles, substituted or unsubstituted benzimidazoles, substituted or unsubstituted indazoles, substituted or unsubstituted azaindazoles, substituted or unsubstituted isoindoles, substituted or unsubstituted carbazoles, substituted or unsubstituted P-Carbolines (9H-pyrido[3,4-b]indoles), substituted or unsubstituted pinolines, substituted or unsubstituted ibogamines, and substituted or unsubstituted harmines. Hetero aromatic amines disclosed above may be substituted, provided that there is a free NH that can participate in the cross-coupling reactions.

[0084] Examples of amides compatible with these reaction conditions include, but are not limited to, substituted or unsubstituted primary amides, substituted or unsubstituted secondary amides, and substituted or unsubstituted cyclic amides. Substituted or unsubstituted cyclic amides include, but are not limited to, substituted or unsubstituted [i-lactams. substituted or unsubstituted y-lactams, substituted or unsubstituted 5-lactams, and substituted or unsubstituted c-lactams. Amides disclosed abovemay be substituted, provided that there is a free NH that can participate in the cross-coupling reactions.

[0085] Substituted or unsubstituted cyclic amides include, but are not limited to, substituted or unsubstituted 2-azetidinone, substituted or unsubstituted pyrrolidin-2-one, substituted or unsubstituted pyrrolidine-2, 5-dione, substituted or unsubstituted piperidin-2-one, substituted or unsubstituted piperidin-2, 6-dione, substituted or unsubstituted azepan-2-one, substituted or unsubstituted indolin-2-one, substituted or unsubstituted isoindo lin-1 -one, substituted or unsubstituted isoindoline- 1,3 -dione, substituted or unsubstituted 3,4-dihydroisoquinolin-l(2H)-one, substituted or unsubstituted 3,4-dihydroquinolin-2(lH)-one, substituted or unsubstituted isoindoline- 1,3-dithione, substituted or unsubstituted benzo[d]oxazol-2(3H)-one, substituted or unsubstituted lH-benzo[d]imidazol-2(3H)-one, substituted or unsubstituted benzo[d]thiazol-2(3H)-one, substituted or unsubstituted phthalimide, substituted or unsubstituted cyclohexane- 1,2-dicarboximide, and substituted or unsubstituted cyclopentane- 1,2-dicarboximide. Cyclic amides disclosed above may be substituted, provided that there is a free NH that can participate in the cross-coupling reactions.

[0086] In another aspect, described herein is a compound having one of the following structures:wherein,R1is H or C1-C6alkyl; and R8is a substituted or unsubstituted heteroaromatic comprising a NH, or a substituted or unsubstituted amide comprising a NH.

[0087] Non-limiting exemplary cubanes prepared with the copper-mediated amination methodology include:

[0088] The scope of the copper-mediated amination methodology includes heteroaromatic amines and amide functionalities. Multifunctional substrates such as triazole and benzotriazole can be alkylated with complete regioselectivity. Many functional groups of the amine and amide coupling substrates are tolerated in the copper-mediated amination methodology, including ketones, aryl halides, esters, and ethers, thus enabling orthogonal functionalization of the products. This method is therefore a direct, convenient, and general alternative to the Curtins rearrangement for the synthesis of aminated cubanes. Such motifs are desirable since they can act as bioisosteres of anilines, which are structural alerts for drug discovery due to their tendency for oxidative arene metabolism leading to adverse idiosyncratic drug reactions.C-C cross coupling of cubanes - Alkylation

[0089] Disclosed herein is a novel, unified mechanistic platform designed for coupling cubanyl radicals with both C(sp3)- and C(sp2)-fragments. Radical-mediated halide abstraction from alkyl and aryl bromides to generate alkyl and aryl radicals is paired with a reductively generated cubyl radical derived from a redox-active ester. In some embodiments, the radical-mediated halide abstraction is silyl radical-mediated halide abstraction, germanyl radical-mediated halide abstraction, aryl radical- mediated halide abstraction, α-a mino radical-mediated halide abstraction, or stannyl radical- mediated halide abstraction. In some embodiments, the radical-mediated halide abstraction is silyl radical-mediated halide abstraction or germanyl radical-mediated halide abstraction. In some embodiments, the radical -mediated halide abstraction is silyl radical-mediated halide abstraction. Both alkyl snd aryl radicals can then undergo radical cross-coupling via copper catalysis. To prevent decomposition of the electrophilic redox-active ester, a non-nucleophilic tertiary aminosilane is used, aminosilane 32.Scheme 8. C-C cross coupling of cubanes°x ■R5photocatalyst, copper catalyst+ R5-Br aminosilane 32 MeO2C0 o base, irradiationMeO2C r or

[0090] The process for the alkylation of a cubane comprises metallaphotoredox catalysis of a cubane comprising a redox active ester with a substituted or unsubstituted C1-C6alkyl halide. In some embodiments, the metallaphotoredox catalysis involves combining a cubane comprising a redox active ester, a substituted or unsubstituted C1-C6alkyl halide, a halogen atom abstractor, a suitable photocatalyst, a suitable copper catalyst, and a suitable base, and irradiating the mixture at a suitable wavelength.

[0091] In some embodiments, the redox active ester is -C(=O)-O-N-succinimidyl, -C(=O)-O-N- phthalimidyl, -C(=O)-O-N-tetrachlorophthalimidyl, -C(=O)-Obt, or -C(=O)-Oat. In some embodiments, the redox active ester is -C(=O)-O-N-succinimidyl, -C(=O)-O-N-phthalimidyl, - C(=O)-O-N-tetrachlorophthalimidyl, or -C(=O)-O-N-l,8-naphthalimidyl. In some embodiments, the redox active ester is -C(=O)-O-N-phthalimidyl or -C(=O)-O-N-tetrachlorophthalimidyl. In someembodiments, the redox active ester is -C(=O)-O-N-phthalimidyl. In some embodiments, the redox active ester is -C(=O)-O-N-tetrachlorophthalimidyh In some embodiments, the redox active ester is -C(=O)-O-N - 1 , 8-naphthalimidyl.

[0092] In some embodiments, the halogen atom abstractor is a silane. In some embodiments, the halogen atom abstractor is a silane comprising a Si-OH moiety, a Si-N bond, or a Si-O-N moiety. In some embodiments, the halogen atom abstractor is tris(trimethylsilyl)silanol, N- tris(trimethylsilyl)silyladamantan- 1 -amine, N- tris(trimethylsilyl)silyl-tert-butylamine, N-methyl-N- tris(trimethylsilyl)silyl-tert-butylamine, or N-tris(trimethylsilyl)silylmesitylamine.

[0093] In some embodiments, the halogen atom abstractor is a germane. In some embodiments, the halogen atom abstractor is a germane comprising a Ge-OH moiety, a Ge-N bond, or a Ge-O-Nor substituted or unsubstituted amino; p is 0, 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; and the sum of p and q is 4. In some embodiments, the halogen atom abstractor is tris(trimethylsilyl)germanol, N- tris(trimethylsilyl)germanyladamantan-l -amine, N- tris(trimethylsilyl)germanyl-tert-butylamine, N- methyl-N-tris(trimethylsilyl)germanyl-tert-butylamine, or N- tris(trimethylsilyl)germanylmesitylamine.

[0094] In some embodiments, the halogen atom abstractor is a silane or a germane. In some embodiments, the halogen atom abstractor is a silane comprising a Si-OH moiety, a Si-N bond, or a Si-O-N moiety, or a germane comprising a Ge-OH moiety, a Ge-N bond, or a Ge-O-N moiety.

[0095] In some embodiments, the halogen atom abstractor is an amine. In some embodiments, the halogen atom abstractor is an amine comprising an a-C(sp3)-H bond. In some embodiments, the halogen atom abstractor is an amine comprising 1, 2, 3, 4, 5, 6, 7, or 8 a-C(sp3)-H bond(s). In some embodiments, the halogen atom abstractor is an amine comprising 1, 2, 3, 4, 5, or 6 a-C(sp3)-H bond(s). In some embodiments, the halogen atom abstractor is an amine comprising 2, 4, 6, or 8 a- C(sp3)-H bond(s). In some embodiments, the halogen atom abstractor is EtsN, (‘Pr^NEt, 1,4- Diazabicyclo[2.2.2]octane (DABCO), BngN, (isobutyl)3N, 1,2,2,6,6-Pentamethylpiperidine (PMP), (nBu)3N, or 2,2,6,6-Tetramethylpiperidine (TMP).

[0096] In some embodiments, the halogen atom abstractor is an aryl radical. In some embodiments, the aryl radical is generated from an aryl diazonium salt of formula ArNzX, wherein X is PFe, BF4, OTf, OTs, F, Br, or Cl. In some embodiments, the aryl radical is generated from a diaryliodium saltof formula (Ar)2IX, wherein each Ar is independently substituted or unsubstituted C6-C10aryl, and X is PFs, BF4, OTf, OTs, F, Br, or Cl. In some embodiments, the aryl radical is generated from a substituted or unsubstituted aryl iodide. In some embodiments, the aryl radical is a substituted or unsubstituted iodobenzene. In some embodiments, the aryl radical is generated from a substituted or unsubstituted aryl bromide.

[0097] In some embodiments, the suitable photocatalyst is a heterogeneous photocatalyst or a homogeneous photocatalyst. In some embodiments, the suitable photocatalyst is an organic photocatalyst, organometallic photocatalyst, or inorganic photocatalyst. In some embodiments, the suitable photocatalyst is an iridium photocatalyst. In some embodiments, the suitable photocatalyst is a ruthenium photocatalyst. In some embodiments, the suitable photocatalyst is a copper photocatalyst. In some embodiments, the suitable photocatalyst is an organic photocatalyst. In some embodiments, the suitable photocatalyst is an organic photocatalyst comprising a substituted or unsubstituted cyanobenzene. In some embodiments, the suitable photocatalyst is Eosin Y, 1, 2,3,5- tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4-CzIPN), 2,4,5,6-tetrakis(9H-carbazol-9-yl) isophthalonitrile, Ir(dF(CF3))2(dtbbpy)PF6, Ir(ppy)3, Ir(dFppy)3, Ir(ppy)2(dOMebpy)PF6, Ir(ppy)2(dtbbpy)PF6, Ir(ppy)2(bpy)PF6, Ir(FMeppy)2(dtbbpy)PF6, Ir(dFMeppy)2(dtbbpy)PF6, Ir(dFMeppy)2(bpy)PF6, Ir(dF (F)ppy)2(dtbbpy)PF6, Ir(dF (CF3)ppy)2(bpy)PF e, Ir(dF (CF3)ppy)2(4,4 ’ - dFbpy)PF6, Ir(dF(CF3)ppy)2(5,5’-dFbpy)PF6, Ru(bpy)3Cl2, or [Ru(4,4’-d(Cl)(bpy)3](PF6)2. In some embodiments, the suitable photocatalyst is l,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4- CzIPN) or 2,4,5,6-tetrakis(9H-carbazol-9-yl) isophthalonitrile. In some embodiments, the suitable photocatalyst is Ir(dF(CF3))2(dtbbpy)PF6, Ir(ppy)3, Ir(dFppy)3, Ir(ppy)2(dOMebpy)PF6, Ir(ppy)2(dtbbpy)PF6, Ir(ppy)2(bpy)PF6, Ir(FMeppy)2(dtbbpy)PF6, Ir(dFMeppy)2(dtbbpy)PF6, Ir(dFMeppy)2(bpy)PF6, Ir(dF(F)ppy)2(dtbbpy)PF6, Ir(dF(CF3)ppy)2(bpy)PF6, Ir(dF(CF3)ppy)2(4,4’- dFbpy)PFe, or Ir(dF(CF3)ppy)2(5,5’-dFbpy)PF6. In some embodiments, the suitable photocatalyst is Ru(bpy)3Cl2or [Ru(4,4’-d(Cl)(bpy)3](PF6)2.

[0098] In some embodiments, the suitable copper catalyst is a copper (I) catalyst or copper (II)

[0099] In some embodiments, the suitable base is an organic base or inorganic base. In some embodiments, the suitable base is absent.

[0100] In some embodiments, the suitable wavelength is about 380 nm to about 700 nm, about 100 nm to about 280 nm, about 280 nm to about 315 nm, about 315 nm to about 400 nm, about 400 nm to about 440 nm, about 420 nm to about 460 nm, about 400 nm to about 500 nm, about 280 nm to about 600 nm, about 280 nm, about 300 nm, about 320 nm, about 340 nm, about 360 nm, about 380 nm, about 400 nm, about 420 nm, about 440 nm, about 480 nm, about 500 nm, about 520 nm, about 540 nm, about 560 nm, about 580 nm, or about 600 nm. In some embodiments, the suitable wavelength is generated by a light-emitting diode (LED). In some embodiments, the suitable wavelength is generated by an integrated photoreactor.a secondary C1-C6alkyl halide, wherein the C1-C6alkyl is substituted or unsubstituted. In some embodiments, the suitable substituted or unsubstituted C1-C6alkyl halide is a substituted or unsubstituted C1-C6alkyl chloride, a substituted or unsubstituted C1-C6alkyl bromide, or a C1-C6alkyl iodide. In some embodiments, the suitable substituted or unsubstituted C1-C6alkyl halide is generated from an alcohol. In some embodiments, the substituted or unsubstituted C1-C6alkyl halide is generated in-situ from an alcohol. In some embodiments, the suitable substituted or unsubstituted C1-C6alkyl halide is generated in-situ from another substituted or unsubstituted C1-C6alkyl halide with a suitable MX salt, wherein M is an ammonium cation, phosphonium cation, lithium cation, sodium cation, potassium cation, or cesium cation and X is Cl, Br, or I.

[0102] Non-limiting exemplary cubanes prepared with the copper-mediated alkylation of cubanes methodologies include:

[0103] Primary, secondary, and benzylic alkyl bromides can be coupled with the tertiary cubane in good yields. Moreover, many functional groups, including the metal-sensitive isoxazole, can be present on the alkyl bromide during the copper-mediated alkylation reaction.Arylation and Hetero arylation of Cubanes

[0104] Under slightly modified conditions, aryl and heteroaryl bromides can also be coupled with cubanes comprising redox-active esters prepared from tetrachloro -N-hydroxy-phthalimide.Scheme 9. Arylation of cubanes

[0105] The process for the preparation of an aryl-cubane or heteroaryl-cubane comprises metallaphotoredox catalysis of a cubane comprising a redox active ester with a substituted or unsubstituted C6-C10aryl halide or a substituted or unsubstituted 5-10 membered heteroaryl halide.

[0106] In some embodiments, the metallaphotoredox catalysis comprises combining a cubane comprising a redox active ester, a substituted or unsubstituted C6-C10aryl halide, a halogen atom abstractor, a suitable photocatalyst, a suitable copper catalyst, and a suitable base, and irradiating the mixture at a suitable wavelength.

[0107] In some embodiments, the redox active ester is -C-O-N-succinimidyl, -C(=O)-O-N- phthalimidyl, -C(=O)-O-N-tetrachlorophthalimidyl, -C(=O)-OBt, or -C(=O)-OAt. In some embodiments, the redox active ester is -C(=O)-O-N-succinimidyl, -C(=O)-O-N-phthalimidyl, -C(=O)-O-N-tetrachlorophthalimidyl, or -C(=O)-O-N-l,8-naphthalimidyl. In some embodiments, the redox active ester is -C(=O)-O-N-phthalimidyl or -C(=O)-O-N-tetrachlorophthalimidyl. In some embodiments, the redox active ester is -C(=O)-O-N-phthalimidyl. In some embodiments, the redox active ester is -C(=O)-O-N-tetrachlorophthalimidyl. In some embodiments, the redox active ester is -C(=O)-O-N- 1 ,8-naphthalimidyl.

[0108] In some embodiments, a C6-C10aryl halide, redox-active ester S6, a halogen atom abstractor, a suitable photocatalyst, a suitable copper catalyst, and a suitable base, in a suitable solvent can be irradiated, for example, using a photoreactor.

[0109] In some embodiments, the halogen atom abstractor is a silane. In some embodiments, the halogen atom abstractor is a silane comprising a Si-OH moiety, a Si-N bond, or a Si-O-N moiety. In some embodiments, the halogen atom abstractor is tris(trimethylsilyl)silanol, N- tris(trimethylsilyl)silyladamantan- 1 -amine, N-tris(trimethylsilyl)silyl-tert-butylamine, N-methyl-N- tris(trimethylsilyl)silyl-tert-butylamine, orN-tris(trimethylsilyl)silylmesitylamine.

[0110] In some embodiments, the halogen atom abstractor is a germane. In some embodiments, the halogen atom abstractor is a germane comprising a Ge-OH moiety, a Ge-N bond, or a Ge-O-N moiety. In some embodiments, the halogen atom abstractor is tris(trimethylsilyl) germanol, N- tris(trimethylsilyl)germanyladamantan-l -amine, N- tris(trimethylsilyl)germanyl-tert-butylamine, N- methyl-N-tris(trimethylsilyl)germanyl-tert-butylamine, or N- tris(trimethylsilyl)germanylmesitylamine.

[0111] In some embodiments, the halogen atom abstractor is a silane or a germane. In some embodiments, the halogen atom abstractor is a silane comprising a Si-OH moiety, a Si-N bond, or a Si-O-N moiety; or is a germane comprising a Ge-OH moiety, a Ge-N bond, or a Ge-O-N moiety.

[0112] In some embodiments, the halogen atom abstractor is an amine. In some embodiments, the halogen atom abstractor is an amine comprising an a-C(sp3)-H bond. In some embodiments, the halogen atom abstractor is an amine comprising 1, 2, 3, 4, 5, 6, 7, or 8 a-C(sp3)-H bond(s). In some embodiments, the halogen atom abstractor is an amine comprising 1, 2, 3, 4, 5, or 6 a-C(sp3)-Hbond(s). In some embodiments, the halogen atom abstractor is an amine comprising 2, 4, 6, or 8 a- C(sp3)-H bond(s). In some embodiments, the halogen atom abstractor is EtgN, (‘Pr^NEt, 1,4- Diazabicyclo[2.2.2]octane (DABCO), BnsN, (isobutyl^N, 1,2,2,6,6-Pentamethylpiperidine (PMP), (nBu)3N, or 2,2,6,6-Tetramethylpiperidine (IMP).

[0113] In some embodiments, the halogen atom abstractor is an aryl radical. In some embodiments, the aryl radical is generated from an aryl diazonium salt of formula ArN2X, wherein Ar is substituted or unsubstituted aryl and X is PFe, BF4, OTf, OTs, F, Br, or Cl. In some embodiments, the aryl radical is generated from a diaryliodium salt of formula (Ar)2lX, wherein each Ar is independently substituted or unsubstituted aryl and X is Pi e, BF4, OTf, OTs, F, Br, or Cl. In some embodiments, the aryl radical is generated from a substituted or unsubstituted aryl iodide. In some embodiments, the aryl radical is a substituted or unsubstituted iodobenzene. In some embodiments, the aryl radical is generated from a substituted or unsubstituted aryl bromide.

[0114] In some embodiments, the halogen atom abstractor is added in an amount equivalent to about 1 equivalent to about 2.0 equivalents relative to cubane. In some embodiments, the halogen atom abstractor is added in an amount equivalent to about 1.3 equivalents, about 1.4 equivalents, about 1.5 equivalents, about 1.6 equivalents, about 1.7 equivalents, about 1.8 equivalents, about 1.9 equivalents, or about 2.0 equivalents relative to cubane.

[0115] In some embodiments, the suitable photocatalyst is an organic photocatalyst or inorganic photocatalyst. In some embodiments, the suitable photocatalyst is an iridium photocatalyst. In some embodiments, the suitable photocatalyst is a ruthenium photocatalyst. In some embodiments, the suitable photocatalyst is a copper photocatalyst. In some embodiments, the suitable photocatalyst is an organic photocatalyst. In some embodiments, the suitable photocatalyst is an organic photocatalyst comprising a substituted or unsubstituted cyanobenzene. In some embodiments, the suitable photocatalyst is Eosin Y, l,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4-CzIPN), 2,4,5,6-tetrakis(9H-carbazol-9-yl) isophthalonitrile, Ir(dF(CF3))2(dtbbpy)PF6, Ir(ppy)3, Ir(dFppy)3, Ir(ppy)2(dOMebpy)PF6, Ir(ppy)2(dtbbpy)PFe, Ir(ppy)2(bpy)PF6, Ir(FMeppy)2(dtbbpy)PF6, Ir(dFMeppy)2(dtbbpy)PF6, Ir(dFMeppy)2(bpy)PFe, Ir(dF (F)ppy)2(dtbbpy)PFe, Ir(dF(CF3)ppy)2(bpy)PFe, Ir(dF(CF3)ppy)2(4,4’-dFbpy)PFe, Ir(dF(CF3)ppy)2(5,5’-dFbpy)PF6, Ru(bpy)3Ch, or [Ru(4,4’-d(Cl)(bpy)3](PF6)2. In some embodiments, the suitable photocatalyst is 1 ,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4-CzIPN) or 2,4,5,6-tetrakis(9H-carbazol-9-yl) isophthalonitrile. In some embodiments, the suitable photocatalyst is Ir(dF(CF3))2(dtbbpy)PF6, Ir(ppy)3, Ir(dFppy)3, Ir(ppy)2(dOMebpy)PF6, Ir(ppy)2(dtbbpy)PF6, Ir(ppy)2(bpy)PF6, Ir(FMeppy)2(dtbbpy)PF6, Ir(dFMeppy)2(dtbbpy)PF6, Ir(dFMeppy)2(bpy)PF e,

[0116] In some embodiments, the suitable photocatalyst is added in an amount equivalent to about 0.05 mol% to about 2 mol%. In some embodiments, the suitable photocatalyst is added in an amount equivalent to about 0.05 mol%, about 0.1 mol%, about 0.2 mol%, about 0.3 mol%, about 0.4 mol%, about 0.5 mol%, about 0.6 mol%, about 0.7 mol%, about 0.8 mol%, about 0.9 mol%, about 0.5 mol%, about 1 mol%, about 1.5 mol%, or about 2 mol%.

[0117] In some embodiments, the suitable copper catalyst is a copper (I) catalyst or copper (II)

[0118] In some embodiments, the suitable copper catalyst is added in an amount equivalent to about 5 mol% to about 65 mol%. In some embodiments, the suitable copper catalyst is added in an amount equivalent to about 5 mol%, about 10 mol%, about 15 mol%, about 20 mol%, about 25 mol%, about 30 mol%, about 35 mol%, about 40 mol%, about 45 mol%, about 50 mol%, about 55 mol%, about 60 mol%, or about 65 mol%. In some embodiments, the suitable copper catalyst is added in an amount equivalent to about 20 mol%. In some embodiments, the suitable copper catalyst is added in an amount equivalent to about 65 mol%.

[0119] In some embodiments, the suitable base is sodium acetate and the suitable solvent is acetone.

[0120] In some embodiments, the halide of the substituted or unsubstituted C6-C10aryl halide or substituted or unsubstituted 5-10 membered heteroaryl halide is Br or I. In some embodiments, the halide of the substituted or unsubstituted C6-C10aryl halide or substituted or unsubstituted 5-10 membered heteroaryl halide is Br.

[0121] In some embodiments, the substituted or unsubstituted C6-C10aryl of the substituted or unsubstituted C6-C10aryl halide is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl. In some embodiments, the substituted or unsubstituted 5-10 membered heteroaryl of the substituted or unsubstituted 5-10 membered heteroaryl halide is substituted or unsubstitutedpyridinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted furazanyl, substituted or unsubstituted indolizinyl, substituted or unsubstituted indolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted benzofurazanyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted purinyl, substituted or unsubstituted quinolizinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted cinnolinyl, substituted or unsubstituted phthalazinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted 1,8- naphthyridinyl, substituted or unsubstituted furopyridinyl, or substituted or unsubstituted pteridinyl.

[0122] In some embodiments, the suitable wavelength is about 380 nm to about 700 nm, about 100 nm to about 280 nm, about 280 nm to about 315 nm, about 315 nm to about 400 nm, about 400 nm to about 440 nm, about 420 nm to about 460 nm, about 400 nm to about 500 nm, about 280 nm to about 600 nm, about 280 nm, about 300 nm, about 320 nm, about 340 nm, about 360 nm, about 380 nm, about 400 nm, about 420 nm, about 440 nm, about 480 nm, about 500 nm, about 520 nm, about 540 nm, about 560 nm, about 580 nm, or about 600 nm. In some embodiments, the suitable wavelength is generated by a light-emitting diode (LED). In some embodiments, the suitable wavelength is generated by an integrated photoreactor.

[0123] In another aspect, described herein is a compound having one of the following structures:wherein,R1is H or C1-C6alkyl; and R9is a substituted or unsubstituted C6-C10aryl or a substituted or unsubstituted 5-10 membered heteroaryl, provided that R9is not phenyl substituted with one substituent selected from Cl, CN, and CF3or 3-chloroindazolyl.

[0124] In some embodiments, R9is a substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl. In some embodiments, R9is a substituted or unsubstituted phenyl. In some embodiments, R9is a substituted or unsubstituted naphthyl.

[0125] In some embodiments, R9is a substituted or unsubstituted pyridinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted tetrazo lyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted furazanyl, substituted or unsubstituted indolizinyl, substituted or unsubstituted indolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted benzofurazanyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted purinyl, substituted or unsubstituted quinolizinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted cinnolinyl, substituted or unsubstituted phthalazinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted 1,8-naphthyridinyl substituted or unsubstituted furopyridinyl or substituted or unsubstituted pteridinyl. In some embodiments, R9is a substituted or unsubstituted pyridinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, or substituted or unsubstituted furazanyl. In some embodiments, R9is a substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted orunsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, or substituted or unsubstituted triazinyl. In some embodiments, R9is a substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, or substituted or unsubstituted furazanyl. In some embodiments, R9is a substituted or unsubstituted indolizinyl, substituted or unsubstituted indolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted benzofurazanyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted purinyl, substituted or unsubstituted quinolizinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted cinnolinyl, substituted or unsubstituted phthalazinyl, or substituted or unsubstituted quinazolinyl.

[0126] Exemplary aryl and heteroaryl cubanes prepared using this methodology include the following cubanes:

[0127] Synthetically useful functional groups such as cyanides and chlorides can be preserved during the arylation and heteroarylation reactions. Of note is the tolerance of an ori / zo-substituent on the phenyl in the coupling reactions.Trifluoromethylation of Cubanes

[0128] Disclosed herein is a trifluoromethylation process for cubanes that is based on pairing of oxidative decarboxylation of cubane 16 with reductive trifluoromethyl radical generation.Scheme 11. Trifluoromethylation of Cubanes

[0129] The process for the trifluoromethylation of cubane comprises the oxidative decarboxylation of a cubane-carboxylic acid in the presence of an electrophilic trifluoromethylation reagent.

[0130] In some embodiments, the electrophilic trifluoromethylation reagent is selected from:; wherein each R13is independently -Me, -Et, -F, -Cl, -OMe, or -Ph; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and each R14is independently substituted or unsubstituted C1-C4alkyl or substituted or unsubstituted C6-C10aryl.

[0131] In some embodiments, oxidative decarboxylation of the cubane-carboxylic acid comprises mixing the cubane-carboxylic acid with a suitable photocatalyst, a suitable copper catalyst, and a suitable base, and irradiating the mixture at a suitable wavelength.

[0132] In some embodiments, the suitable photocatalyst is an organic photocatalyst or inorganic photocatalyst. In some embodiments, the suitable photocatalyst is an iridium photocatalyst. In some embodiments, the suitable photocatalyst is a ruthenium photocatalyst. In some embodiments, the suitable photocatalyst is a copper photocatalyst. In some embodiments, the suitable photocatalyst is an organic photocatalyst. In some embodiments, the suitable photocatalyst is an organic photocatalyst comprising a substituted or unsubstituted cyanobenzene. In some embodiments, the suitable photocatalyst is Eosin Y 1 2 3 5 tetrakis(carbazol 9 yl) 4 6 dicyanobenzene (4 CzIPN)

[0133] In some embodiments, the suitable copper catalyst is a copper (I) catalyst or copper (II)

[0134] In some embodiments, bis(2,5-dimethylphenyl)(trifluoromethyl)sulfonium trifluoromethanesulfonate, cubane 16, a suitable photocatalyst, a suitable copper catalyst, and a suitable base, in a suitable solvent can be irradiated at, e.g., 450 nm. In some embodiments, the suitable photocatalyst is Ir(dF(CF3)ppy)2(4,4’-d(CF3)bpy)PF6. In some embodiments, the suitable copper catalyst is Cu(acac)2, Cu(et)2, Cu(DMH)2, Cu(Tbu)2, or Cu(flacac)2. In some embodiments, the suitable base is sodium carbonate. In some embodiments, the suitable solvent is dimethylsulfoxide.

[0135] In some embodiments, the suitable wavelength is about 380 nm to about 700 nm, about 100 nm to about 280 nm, about 280 nm to about 315 nm, about 315 nm to about 400 nm, about 400 nm to about 440 nm, about 420 nm to about 460 nm, about 400 nm to about 500 nm, about 280 nm to about 600 nm, about 280 nm, about 300 nm, about 320 nm, about 340 nm, about 360 nm, about 380 nm, about 400 nm, about 420 nm, about 440 nm, about 480 nm, about 500 nm, about 520 nm, about 540 nm, about 560 nm, about 580 nm, or about 600 nm. In some embodiments, the suitable wavelength is generated by a light-emitting diode (LED). In some embodiments, the suitable wavelength is generated by an integrated photoreactor.

[0136] Trifluoromethylated cubanes prepared with the methodology described herein include:Definitions

[0137] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include”, “includes”, and “included” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0138] A “redox active ester” is an ester functional group that is able to accept an electron from a single electron transfer (SET) event. Redox-active esters include, but are not limited to, N-hydroxy- phthalimide esters, N-hydroxy-tetrachlorophthalimide esters, thiohydroxamate esters (also known as Barton esters), in situ esters derived from l-hydroxy-7-azabenzotriazole (HOAt), in situ esters derived from hydroxybenzotriazole (HOBt), and iodomesitylene dicarboxylates. In some embodiments, the redox active ester is -C(=O)-O-N-succinimidyl, -C(=O)-O-N-phthalimidyl, -C(=O)-O-N-tetrachlorophthalimidyl, -C(=O)-Obt, or -C(=O)-Oat. In some embodiments, the redox active ester is -C(=O)-O-N-succinimidyl, -C(=O)-O-N-phthalimidyl, -C(=:O)-O-N- tetrachlorophthalimidyl, or -C(=O)-O-N-l,8-naphthalimidyl. In some embodiments, the redox active ester is -C(=O)-O-N-phthalimidyl or -C(=O)-O-N-tetrachlorophthalimidyl. In some embodiments, the redox active ester is -C(=O)-O-N-phthalimidyl. In some embodiments, the redox active ester is -C(=0)-0-N-tetrachlorophthalimidyl, In some embodiments, the redox active ester is -C(=O)-O-N- 1 ,8-naphthalimidyl

[0139] The term “halogen atom abstractor” refers to any reagent that is capable, under suitable conditions (e.g., photoredox conditions), of abstracting a halogen free radical from a substrate generating an organo-radical species.

[0140] As used herein, C1-Cxincludes C1-C2, C1-C3 . . . C1-Cx. By way of example only, a group designated as "C1-C4" indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of

[0141] An “alkyl” group refers to a saturated aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e., a C1-Cioalkyl. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, etc. , up to andincluding 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a C1-Cealkyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, Ao-propyl, n-butyl, Ao-butyl, j-ec-butyl, fibutyl, pentyl, neopentyl, and hexyl. In some embodiments, an alkyl is a C1- C4alkyl. In some embodiments, the alkyl is methyl, ethyl, propyl, wo-propyl, n-butyl, iso-butyl, secbutyl, or i-butyl.

[0142] “Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.

[0143] The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula C(R)=CR2, wherein each R is independently H or an alkyl. In some embodiments, the “alkenyl” group has 2 to 10 carbon atoms, i.e., a C2-Cioalkenyl. In some embodiments, the “alkenyl” group is a C2-C6alkenyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0144] The term “alkynyl” refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkynyl group has the formula -OC-R, wherein R refers to the remaining structures of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, the “alkynyl” group has 2 to 10 carbon atoms, i.e., a C2-Cioalkynyl. In some embodiments, the “alkynyl” group is a C2-C6alkynyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an

[0145] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0146] The term “alkylamino” refers to -N(alkyl)xHy, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

[0147] The term “aromatic” refers to a planar ring having a delocalized n-electron system containing 4n+2 n electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridyl). The term includes monocyclic or fused-ring bicyclic or fused-ring multicyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0148] The terms “carbocyclic” or “carbocycle” refer to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom that isdifferent from carbon. In some embodiments, carbocycles are monocyclic (i.e., a single ring), bicyclic (i.e., two rings), or multicyclic (i.e., three or more rings). In some embodiments, a carbocycle is a monocyclic carbocycle or a bicyclic carbocycle. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, one of the two rings of a bicyclic carbocycle is aromatic, and the point of attachment to the remainder of the compound is at a carbon atom of the aromatic ring. In some embodiments, one of the two rings of a bicyclic carbocycle is aromatic, and the point of attachment to the remainder of the compound is at a carbon atom of the non-aromatic ring. In some embodiments, a bicyclic carbocycle is a fused bicyclic carbocycle. In some embodiments, both rings of a fused bicyclic carbocycle are aromatic (i.e., an aryl). The terms “carbocyclic” or “carbocycle” include cycloalkyl and aryl.

[0149] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In some embodiments, an aryl is a phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a C6-C10aryl.

[0150] The term “cycloalkyl” refers to a cyclic saturated aliphatic hydrocarbon. In some embodiments, cycloalkyl is a monocyclic cycloalkyl (i.e., a single ring), bicyclic cycloalkyl (i.e., two rings), or multicyclic cycloalkyl (i.e., three or more rings). In some embodiments, a cycloalkyl is a C3-C10 cycloalkyl. In other embodiments, a cycloalkyl is a C5-C12 cycloalkyl. In some embodiments, cycloalkyl is a monocyclic cycloalkyl. In some embodiments, cycloalkyl is a bicyclic cycloalkyl. In some embodiments, cycloalkyl is a multicyclic cycloalkyl.

[0151] The term “monocyclic cycloalkyl” refers to cyclic saturated aliphatic hydrocarbon that is a single ring. Monocyclic cycloalkyls include, for example, from 3 to 10 carbon atoms in the ring (i.e., a monocyclic Ca-Ciocycloalkyl). Monocyclic cycloalkyls that include 3 to 10 carbon atoms in the ring include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononane, and cyclodecane. In some embodiments, a monocyclic cycloalkyl is a monocyclic Cs-Cecycloalkyl. Monocyclic Cg-Cecycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0152] The term “bicyclic cycloalkyl” refers to two cycloalkyls that are joined together. In some embodiments, the bicyclic cycloalkyl is a spiro bicyclic (spirocyclic) cycloalkyl, a fused bicyclic cycloalkyl, or a bridged bicyclic cycloalkyl.

[0153] The term “spiro bicyclic cycloalkyl” refers to two cycloalkyls that are joined together and share a single carbon atom. In some embodiments, a spiro bicyclic cycloalkyl has 5 to 12 carbon atoms (i.e., a spiro bicyclic Cs-Cncycloalkyl). Non-limiting examples of spiro bicyclic cycloalkyls include: spiro[2.2]pentyl, spiro[3.2]hexyl, spiro[3.3]heptyl, spiro[4.3]octyl, spiro [4.2]heptyl,spiro[5.3]nonyl, spiro[5.4]decanyl, spiro[5.5]undecanyl, spiro[5.2]octyl, spiro[6.3]decanyl, spiro[6.4]undecanyl, and spiro[6.5]dodecanyl.

[0154] The term “fused bicyclic cycloalkyl” refers to two cycloalkyls that are joined together and share two adjacent carbon atoms. In some embodiments, a fused bicyclic cycloalkyl has 5 to 12y y y y [ ] y [ ] bicyclo[4.2.0]octane, bicyclo[4.1.0]heptane, bicyclo [3.3.0] octane, and bicyclo[3.1.0]hexane.

[0155] The term “bridged bicyclic cycloalkyl” refers to two cycloalkyls that are joined together and share three or more carbon atoms. In some embodiments, a bridged bicyclic cycloalkyl has 5 to

[0157] The term “multicyclic cycloalkyl” refers to three or more cycloalkyls joined together and each cycloalkyl shares at least one carbon atom with at least one other cycloalkyl. In some embodiments, a multicyclic cycloalkyl has 8 to 12 carbon atoms (i.e., a multicyclic Cg- Ci2cycloalkyl). In some embodiments, multicyclic cycloalkyls include caged cycloalkyls, spiro cycloalkyls, fused cycloalkyls, bridged cycloalkyls, or a combination thereof. In some embodiments,

[0158] The term “caged cycloalkyl” refers to a subset of multicyclic cycloalkyls having a three- dimensional enclosed structure with each ring forming a face of the three-dimensional structure.

[0160] The term “cycloalkenyl” refers to a type of non-aromatic cycloalkyl group in which at least one carbon-carbon double bond is present. In some embodiments, a cycloalkenyl is a monocyclic cycloalkenyl, a bicyclic cycloalkenyl, or a multicyclic cycloalkenyl. In some embodiments, a cycloalkenyl is a monocyclic cycloalkenyl. In some embodiments, a cycloalkenyl is a bicyclic cycloalkenyl. In some embodiments, a cycloalkenyl is a multicyclic cycloalkenyl.

[0161] In some embodiments, a monocyclic cycloalkenyl has 5 to 12 carbon atoms (i.e., a Cs- Ci2cycloalkenyl). In some embodiments, a monocyclic cycloalkenyl has 5 to 8 carbon atoms (i.e., a Cs-Cncycloalkenyl). Non-limiting examples of cycloalkenyls include:

[0162] The term “bicyclic cycloalkenyl” refers to two cycloalkyls that are joined together, wherein at least one of the cycloalkyls has at least one carbon-carbon double bond. In some embodiments, thebicyclic cycloalkenyl is a spiro bicyclic cycloalkenyl, a fused bicyclic cycloalkenyl, or a bridged bicyclic cycloalkenyl.

[0163] The term “spiro bicyclic cycloalkenyl” refers to two cycloalkyls that are joined together and share a single carbon atom and at least one of the cycloalkyls has at least one carbon-carbon double bond. In some embodiments, a spiro bicyclic cycloalkenyl has 6 to 12 carbon atoms (i.e., a spiro

[0164] The term “fused bicyclic cycloalkenyl” refers to two cycloalkyls that are joined together and share two adjacent carbon atoms and at least one of the cycloalkyls has at least one carboncarbon double bond. In some embodiments, a fused bicyclic cycloalkenyl has 6 to 12 carbon atoms

[0165] The term “bridged bicyclic cycloalkenyl” refers to two cycloalkyls that are joined together and share three or more carbon atoms and at least one of the cycloalkyls has at least one carboncarbon double bond. In some embodiments, a bridged bicyclic cycloalkenyl has 6 to 12 carbon

[0166] The term “heterocycle” or “heterocyclic” refers to hetero aromatic rings (also known as heteroaryls) and hetero non-aromatic rings (also known as heterocycloalkyl rings or hetero alicyclic groups or saturated heterocycles) containing one to six heteroatoms in the ring(s), where eachheteroatom in the ring(s) is selected from nitrogen, oxygen, sulfur, boron, and phosphorus, where each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent 0 or S atoms. In some embodiments, heterocycles are monocyclic (i.e., a single ring), bicyclic (i.e., two rings), or multicyclic (i.e., three or more rings). In some embodiments, a heterocycle is a monocyclic heterocycle or a bicyclic heterocycle. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, one of the two rings of a bicyclic heterocycle is aromatic, and the point of attachment to the remaining of the compound is at a carbon atom or heteroatom of the aromatic ring. In some embodiments, one of the two rings of a bicyclic heterocycle is aromatic, and the point of attachment to the remaining of the compound is at a carbon atom or heteroatom of the non-aromatic ring. In some embodiments, bicyclic heterocycle is a fused bicyclic heterocycle. In some embodiments, both rings of a fused bicyclic heterocycle are aromatic (i.e., a heteroaryl). Heterocycle groups are either C-attached (or C-linked) or TV-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol- 1-yl (TV-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both TV-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).

[0167] Examples of bicyclic heterocycles include, but are not limited to, 3H-indolyl, indolin-2- onyl, isoindolin-l-onyl, isoindoline- 1, 3 -dionyl, 3,4-dihydroisoquinolin-l(2H)-onyl, 3,4- dihydroquinolin-2(lH)-onyl, isoindoline- 1, 3-dithionyl, benzo [d]oxazol-2(3H)-onyl, 1H- benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of bicyclic heterocycle also include benzo-fused ring systems, wherein benzene is fused to a monocyclic heteroaromatic ring or a monocyclic heterocycloalkyl ring.

[0168] Examples of aromatic heterocycles include, but are not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.

[0169] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aromatic ring system that has 5-12 atoms that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include, but are not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include, but are not limited to, indolizine, indole, benzofuran, benzothiophene, benzofurazan, benzothiazole, benzoxazole, indazole, benzimidazole, purine, quinolizine, quinazoline, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8- naphthyridine, furopyridine and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring system. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring system. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring system. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring system. In some embodiments, a heteroaryl contains 0-4 N atoms, 1 O atom, and 0-1 S atoms in the ring system. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atom, and 1 S atoms in the ring system. In some embodiments, a heteroaryl is a 5-12 membered heteroaryl. In some embodiments, a monocyclic heteroaryl is a 5-10 membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a 6-10 membered heteroaryl.

[0170] A “heterocycloalkyl” or “hetero alicyclic” group refers to a cycloalkyl group where at least one or more ring carbon atoms has been replaced by one or more heteroatoms selected from nitrogen (N, NH, or N(alkyl)), oxygen, sulfur (S, SO, or SO2), boron (B, BH, B-OH, B-alkoxy, B-alkyl), or phosphorus. Non-aromatic heterocycles are optionally substituted with one or two oxo (=0) moieties, such as pyrrolidin-2-one. In some embodiments, heterocycloalkyl is a monocyclic heterocycloalkyl (i.e., a single ring), bicyclic heterocycloalkyl (i.e., two rings), or multicyclic heterocycloalkyl (i.e., three or more rings). In some embodiments, heterocycloalkyl is a monocyclic heterocycloalkyl. In some embodiments, heterocycloalkyl is a bicyclic heterocycloalkyl. In some embodiments, heterocycloalkyl is a multicyclic heterocycloalkyl. In one aspect, a heterocycloalkyl is a 3-10 membered heterocycloalkyl. In another aspect, a heterocyclo alkyl is a 4-12membered iheterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring system. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring system.

[0171] The term “monocyclic heterocycloalkyl” refers to a heterocycloalkyl that is a single ring. Monocyclic heterocycloalkyls can include from 2 to 9 carbon atoms in the ring for a total of 3 to 10 atoms in the ring. Monocyclic heterocycloalkyls that include 2 to 9 carbon atoms in the ring include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, oxetanyl, thietanyl, thioxanyl, oxazolidinonyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, dihydropyranyl, tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6-tetrahydropyridinyl, piperidin-2-onyl, pyrrolidine-2, 5-dithionyl, pyrrolidine-2, 5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, thiazolidin-2-onyl, pyrrolin-2-yl, pyrrolin-3-yl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl. In some embodiments, monocyclic heterocycloalkyls that include 2 to 8 carbon atoms in the ring include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, and homopiperidinyl. In one aspect, a monocyclic heterocycloalkyl is a monocyclic 3-10 membered heterocycloalkyl. In another aspect, a monocyclic heterocycloalkyl is a monocyclic 4-10 membered heterocycloalkyl. In some embodiments, a monocyclic heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a monocyclic heterocyclo alkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

[0172] The term “bicyclic heterocycloalkyl” refers to two cycloalkyl rings that are joined together and share at least one atom, where at least one ring carbon atom of either or both cycloalkyl rings has been replaced by one or more heteroatoms selected from nitrogen (N, NH, or N(alkyl)), oxygen, sulfur (S, SO, or SO2), boron (B, BH, B-OH, B-alkoxy, B-alkyl), or phosphorus. In some embodiments, a bicyclic heterocycloalkyl has 5-12 ring atoms. In some embodiments, the bicyclic heterocycloalkyl is a spiro bicyclic (spirocyclic) heterocycloalkyl, a fused bicyclic heterocycloalkyl, or a bridged bicyclic heterocycloalkyl.

[0173] The term “spiro bicyclic heterocycloalkyl” refers to two cycloalkyl rings that are joined together and share one atom, where at least one ring carbon atom of either or both cycloalkyl rings has been replaced by one or more heteroatoms selected from nitrogen (N, NH, or N(alkyl)), oxygen, sulfur (S, SO, or SO2), boron (B, BH, B-OH, B-alkoxy, B-alkyl), or phosphorus. In some embodiments, a spiro bicyclic heterocycloalkyl has 5 to 12 ring atoms. Non-limiting examples of

[0174] The term “fused bicyclic heterocycloalkyl” refers to two cycloalkyl rings that are joined together and share two adjacent atoms, where at least one ring carbon atom of either or both cycloalkyl rings has been replaced by one or more heteroatoms selected from nitrogen (N, NH, or N(alkyl)), oxygen, sulfur (S, SO, or SO2), boron (B, BH, B-OH, B-alkoxy, B-alkyl), or phosphorus. In some embodiments, a fused bicyclic heterocycloalkyl has 5 to 12 carbon atoms (i.e., a fusedbicyclic 5-12 membered heterocycloalkyl). In some embodiments, a fused bicyclic heterocycloalkyl has 6 to 10 ring atoms. Non-limiting examples of fused bicyclic heterocycloalkyl include:

[0175] The term “bridged bicyclic heterocycloalkyl” refers to two cycloalkyl rings that are joined together and share three or more atoms, where at least one ring carbon atom of either or both cycloalkyl rings has been replaced by one or more heteroatoms selected from nitrogen (N, NH, or N(alkyl)), oxygen, sulfur (S, SO, or SO2), boron (B, BH, B-OH, B-alkoxy, B-alkyl), or phosphorus. In some embodiments, a bridged bicyclic heterocycloalkyl has 5 to 12 ring atoms. In some embodiments, a bridged bicyclic heterocycloalkyl has 5 to 8 ring atoms. Non-limiting examples of

[0176] The term “multicyclic heterocycloalkyl” refers to three or more cycloalkyl rings that are joined together, where at least one ring carbon atom of any one of the cycloalkyl rings has been replaced by one or more heteroatoms selected from nitrogen (N, NH, or N(alkyl)), oxygen, sulfur (S, SO, or SO2), boron (B, BH, B-OH, B-alkoxy, B-alkyl), or phosphorus. In some embodiments, multicyclic heterocycloalkyls include caged heterocycloalkyls, spiro heterocycloalkyls, fused heterocycloalkyls, bridged heterocycloalkyls, or a combination thereof. In some embodiments, a multicyclic heterocycloalkyl is a caged heterocycloalkyl. In some embodiments, a multicyclic heterocycloalkyl has 5 to 12 ring atoms. Non-limiting examples of multicyclic heterocycloalkyls

[0177] The term “caged heterocycloalkyl” refers to a subset of multicyclic heterocycloalkyls having a three-dimensional enclosed structure with each ring forming a face of the three-dimensional

[0178] A “heterocycloalkenyl” refers to a “heterocycloalkyl” that has at least one double bond in the ring. In some embodiments, heterocycloalkenyl is a monocyclic heterocycloalkenyl (i.e., a single ring), bicyclic heterocycloalkenyl (i.e., two rings), or multicyclic heterocycloalkenyl (i.e., three or more rings). In some embodiments, heterocycloalkenyl is a monocyclic heterocycloalkenyl. In some embodiments, heterocycloalkenyl is a bicyclic heterocycloalkenyl. In some embodiments, heterocycloalkenyl is a multicyclic heterocycloalkenyl.

[0179] The term “monocyclic heterocycloalkenyl” refers to a “monocyclic heterocycloalkyl” that has at least one double bond.

[0180] The term “bicyclic heterocycloalkenyl” refers to a “bicyclic heterocycloalkyl” that has at least one double bond.

[0181] The term “spiro bicyclic heterocycloalkenyl” refers to a “spiro bicyclic heterocycloalkyl” that has at least one double bond.

[0182] The term “fused bicyclic heterocycloalkenyl” refers to a “fused bicyclic heterocycloalkenyl” that has at least one double bond.

[0183] The term “bridged bicyclic heterocycloalkenyl” refers to a “bridged bicyclic heterocyclo alkyl” that has at least one double bond.

[0184] The term “multicyclic heterocycloalkenyl” refers to a “multicyclic heterocycloalkyl” that has at least one double bond.

[0185] The term “halo” or, alternatively, “halogen” or “halide” refers to fluoro (F), chloro (Cl), bromo (Br) or iodo (I).

[0186] The term “haloalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a halogen atom. In some embodiments, a haloalkyl is a C1-Cehaloalkyl. In some embodiments, aembodiments, a haloalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 1 -fluoroethyl, 2 -fluoroethyl, difluorochloromethyl, trichloromethyl, dichloromethyl, chloromethyl, 2,2,2-trichloroethyl, and the like.

[0187] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replacedfluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.

[0188] The term “chloroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a chlorine atom. In one aspect, a chloroalkyl is a C1-C6chloroalkyl. In some embodiments, a chloroalkyl is selected from trichloromethyl, dichloromethyl, chloromethyl, 2, 2, 2 -trichloroethyl, and the like.

[0189] The term “heteroalkyl” refers to an alkyl group in which one or more carbon atoms of the alkyl are replaced by an atom other than carbon, e.g., oxygen, sulfur, sulfoxide, sulfone, or nitrogen (e.g., -NH-, -N(alkyl)-), or combinations thereof. A heteroalkyl is attached to the parent molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-Cgheteroalkyl.

[0190] The term “bond” refers to the connection between two atoms.

[0191] The term “moiety” refers to a specific segment or functional group of a molecule.

[0192] The term “optionally substituted” means that the referenced group is or is not substituted with one or more additional groups. The term “substituted” means that the referenced group is substituted with one or more additional groups. The one or more additional group(s) include, but aregroups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0).EXAMPLES

[0193] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way.Materials and methods

[0194] Commercial reagents were purchased from standard commercial suppliers such as SigmaAldrich, TCI, Acros, or Combi-Blocks, and used as received unless otherwise indicated.Dimethyl cubane-l,4-dicarboxylate and 4-methoxycarbonylcubanecarboxylic acid were purchased from Boron Molecular and used as received.

[0195] Dichloromethane and toluene were purified by passage through columns of activated alumina (Pangbom, A. B., et al., Safe and Convenient Procedure for Solvent Purification. Organometallics 15, 1518-1520 (1996)). All other dry solvents were purchased in sure-seal bottles from Sigma-Aldrich or Acros and used without further purification. Organic solutions were concentrated under reduced pressure on a Buchi rotary evaporator.

[0196] Filtrations of heterogeneous mixtures were performed using ChemRus 6 mL, 20 mL or 60 mL disposable filters unless otherwise indicated. Chromatographic purification of products was accomplished on an automated Teledyne Isco CombiFlash™ NextGen 300+ system with attached ELS detector or on a Biotage Isolera™ Spektra System, using Isco RediSep Rf, Isco RediSep Rf gold, Silicycle SiliaSep™, or Biotage Sfar™ high-capacity silica cartridges. Reverse phase HPLC purification was conducted on a Teledyne ISCO ACCQPrep HP150 system. Thin-layer chromatography (TLC) was performed on Analtech 250-micron silica gel plates. Visuahzation was accomplished by fluorescence quenching at 254 or 365 nm, or by reaction with KMnO4 stain.

[0197] Reversed-phase high-performance liquid chromatography was carried out using an Agilent 1100 HPLC-MSD system consisting of a 6 BOB single quadrupole mass-selective detector (MSD), G1315B diode array detector, G2258A autosampler, two G1361 A preparative pumps, one G1379A quaternary pump with degasser, one G1312A binary pump, and three G1364B fraction collectors from Agilent Technologies. System control and data analysis was performed using Agilent’s ChemStation software, revision B.03.01-SR.1. A Waters XBridge C18 OBD Prep Column, 100 A, 5 μm, 19 mm x 150 mm column was used as the stationary phase (Waters Corporation). Gradient elution was carried out using water and acetonitrile as the mobile phase. An aqueous 10% trifluoroacetic acid or 10% ammonium hydroxide solution was added into the mobile phase as a modifier using a static mixer prior to the column, pumped at 1% of the total mobile phase flow rate.

[0198] !H and13C NMR spectra were recorded on a Broker NanoBay A vance III HD NMR 400 MHz instrument or on a Broker A vance III NMR 500 MHz instrument, and are internally referencedNMR 400 MHz and are reported unreferenced. The multiplicity is denoted as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, h = hextet, hept = heptet, m = multiplet, br = broad. High-resolution mass spectra were obtained at Princeton University mass spectrometry facilities. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer or on a Perkin Elmer Spectrum 100 FTIR spectrometer and are reported in wavenumbers (cm1). No melting points were obtained for cubanes due to their decomposition at high temperature.

[0199] All light-mediated reactions were performed in the PennOC Integrated Photoreactor (Le, C. C. et al. A General Small-Scale Reactor To Enable Standardization and Acceleration ofPhotocatalytic Reactions. ACS Cent. Sci. 3, 647-653 (2017)) using an TED module with the indicated wavelength, 100% light intensity, 5200 rpm fans, and 500 rpm stirring unless otherwise indicated. All reactions at a < 0.2 mmol scale were conducted in a multi- 4 vial holder for five 4 mL screw-cap vials. All reactions at a > 0.2 mmol scale were conducted using a standard single- vial holder unless otherwise indicated.

[0200] The following abbreviations and terms have the indicated meanings throughout:g rpm = revolutions per minute m / z = mass-to-charge ratio; ESI-MS=electronspray ionization-mass spectrometryTLC = thin-layer chromatography; LC / MS or LCMS = liquid chromatography-mass spectrometry HPLC = high pressure liquid chromatography; LRMS = low resolution mass spectrometry HPLC-MSD =high pressure liquid chromatography-mass-selective detectorFTIR or IR = Fourier transform infraredNMR = nuclear magnetic resonancePreparation of the acetate intermediate:

[0201] Di-tert-butyl azodicarboxylate (23.03 g, 100 mmol, Combi-Blocks), dry CH2CI2 (16.8 mL, 6 M), and 1 -acetoxybutadiene (17.8 mL, 16.8 g, 1.5 equiv., mixture of cis and trans isomers, Sigma- Aldrich) were heated to 40 °C for 48 h under an N2 atmosphere. Reaction progress was monitored by consumption of the azodicarboxylate by TLC. The mixture was allowed to cool to room temperature, transferred to a 1 L round-bottom flask using CH2CI2, and concentrated using a rotary evaporator. The crude material was dissolved in EtOAc (ca. 200 mL), and the resulting oil (polyacetoxybutadiene) was triturated by the addition of hexane (ca. 100 mL). The liquid phase was concentrated to ca. 150 mL upon which crystallization began. Crystallization was completed by storing in a freezer (ca. 4 h). The solid precipitate was isolated by filtration yielding 17.7 g of the acetate intermediate as a solid. The filtrate was concentrated to ca. 100 mL. As before, additional polyacetoxybutadiene was removed by trituration with hexane leading to the isolation of additional acetate intermediate upon crystallization. Yield: additional 5.12 g as a solid.Elimination to form the Dihydropyridazine 1:

[0202] The acetate intermediate (22.8 g, slightly impure), Pd(OAc)2 (149.5 mg, 1 mol%), PPI13 (698.7 mg, 4 mol%), 1,4-dioxane (133 mL, 0.5 M), and triethylamine (18.6 mL, 2.0 equiv.) were added to a flame-dried 250 mL three neck flask equipped with a stir bar and a reflux condenser under an N2 atmosphere and refluxed for 3 h. The reaction was monitored by the consumption of the acetate intermediate by TLC. The reaction mixture was allowed to cool to room temperature, concentrated, and purified by automatic column chromatography (Biotage, 330 g column, 0-7% EtOAc for 10 column volumes (CVs), 7-10% for 7 CVs, 10-20% for 5 CVs, 20-50% for 5 CVs; loading with CH2CI2). Recrystallization from EtOAc / heptane provided the dihydropyridazine product. Yield: 12.6 g, 44.6 mmol, 45% as a white solid.Example 2: Synthesis of 2,5-dibromo-l,4-benzoquinine

[0203] A solution of iron(III) chloride hexahydrate (5.0 equiv., 130.1 g, 481.5 mmol) in water (480 mL) was added, as a single portion, to a stirred solution of 2,5-dibromo-l,4-hydroquinone (25.8 g, 96.3 mmol) in MeOH (480 mL) in a 5 L Erlenmeyer flask. The resulting mixture was covered with a glass plate and stirred at room temperature for 1 h. The precipitate was collected by filtration, and washed with water (3 x 30 mL) and MeOH (3 x 30 mL). The residue was recrystallized from heptane / CH2Q2. Recrystallization procedure: 100 mL of both heptane and CHzChwere added, and the mixture was heated to reflux. Further CH2CI2 was added until all precipitate was dissolved. The solution was allowed to cool to room temperature at which point crystallization occurred. Crystallization was completed by storing in a freezer (ca. 8 h) and the 2,5-dibromo-l,4- benzoquinone was collected by filtration. Yield: 23.3 g, 87.6 mmol, 91% of yellow crystals.Example 3: In Az / zz-Preparation of the TMS-Protected Dicarbamate

[0204] Di-tert-butyl pyridazine-l,2-dicarboxylate 1, 282.3 mg, 1.0 mmol) was added to an oven dried 40 mL vial equipped with a large cross-shaped stir bar (cooled under an N2 flow). Dry CH2CI2 (20 mL, 0.05 M) was added, and the colorless solution was degassed by sparging with N2 for 10 min while cooling with an ice bath. The reaction vessel was thoroughly sealed with molten parafilm and electrical tape and irradiated in an integrated photoreactor (365 nm, 100% light intensity, 5200 rpm fan speed, 1000 rpm stirring, 5 h).

[0205] The vial was removed from irradiation and the septum was pierced with a thick needle under N2 pressure without completely removing the molten parafilm. 2,6-Lutidine (464 pL, 428 mg, 4.0 mmol, 4.0 equiv.) was added via a 1 mL syringe in one aliquot. The vessel was cooled to -78 °C and TMSOTf (434 pL, 533.4 mg, 2.4 mmol, 2.4 equiv.) was added dropwise over ca. 30 seconds with a 1 mL syringe. Both 2,6-lutidine and TMSOTf were distilled under an N2 atmosphere prior touse and stored in a Schlenk flask under an N2 atmosphere. The vessel was allowed to warm to room temperature over 30 mins by removal of the dry ice bath affording a solution of the IMS protected dicarbamate.

[0206] 2,5-dibromobenzoquinone (797.7 mg, 3.0 mmol, 3.0 equiv.), dry CH2CI2 (30 mL, 0.1 M with respect to the quinone), and MeOH (2 mL, 50 mmol, 50 equiv.) were added to a 100 mL round bottom flask. The reaction mixture was stirred rapidly (750 rpm or faster) as the solution of the TMS-protected dicarbamate, taken up in a 20 mL syringe, was added over 30 seconds. Yield: 80% of the bisalkene 2.

[0207] The mixture was immediately transferred into a 2 L Erlenmeyer flask containing 240 mL Et20, 240 mL pentane, 190 mL acetone, 190 mL water, and ascorbic acid (2.2 g, 12.5 mmol, 12.5 equiv.) in an ice / water bath. The mixture was stirred rapidly (ca. 1250 rpm using a large stir bar (ca. 7 cm length)) until the deep green color faded to a light yellowish / green color (ca. 15 min, depending on the stir bar size and the speed of stirring; stirring for longer than 20 min led to decomposition). The biphasic suspension was washed with water (3 x 250 mL). The combined aqueous phases were back extracted with ether (1 x 250 mL), and the combined organic phases were washed with brine (1 x 250 mL), dried over Na2SOi (large excess), filtered over a fritted glass funnel, and concentrated using a rotary evaporator with the water bath temperature set to 22 °C (max.). During solvent evaporation, the water bath of the rotary evaporator and the flask were covered with aluminum foil to exclude light (together, covering the flask individually prolonged thetime required and thus led to decomposition). Et2O (5 mL) was added, and the solvent was evaporated to ensure crystallization of the hydroquinone byproduct. Pentane (5 mL) was added and evaporated for the same reason. Following evaporation of both solvents, dry toluene (10 mL) was added followed by activated charcoal (50 mg, both more and less charcoal reduced the yield). The mixture was shaken for 1 min before being rapidly filtered through a celite plug (diameter: ca 1.5 cm, height of celite: ca. 2 cm high, slurry with toluene) into an oven-dried 40 mL vial. The flask was washed further with dry toluene (3 x 5 mL), which was also rapidly filtered through the celite plug, to extract the celite. The solution containing 1, 8-dibromotricyclo[4.4.0.02, 5]deca-3,8-diene-7, 10- dione 2 was collected in a vial and used in the following step with no purification.

[0208] The solution of bisalkene 2 from Example 4 was degassed by sparging with N2 for 10 minutes and placed inside an integrated photoreactor (450 nm, 100% light intensity, 5200 rpm fans, 1000 rpm stirring, 16 h). A black suspension of diketone 3 and the monohydrate was obtained. The suspension was placed in a vial and concentrated using a rotary evaporator.

[0209] 30% aqueous KOH (10 mL) was added to the vial containing diketone 3. This vial was heated to 105 °C in a metal heating block while ensuring that the entire liquid phase was covered by the heating block and stirred for ca. 16 h. The yield at this stage was roughly 45%. The aqueous solution was transferred to a 250 mL separating funnel with water (ca. 10-20 mL), washed with Et2O (ca. 30 mL), and acidified with 1 M HC1. NaCl (ca. 10 g) was added, and the aqueous solution was extracted with EtOAc (5 x 100 mL). Following drying over NaaSCL, 1.5 g activated charcoal wasadded, and the mixture was filtered over a celite plug with EtOAc. Silica gel (2 g) was added, and the solvent was removed by evaporation using a rotary evaporator. A water bath temperature of 40 °C was used and the vacuum was no lower than 40 torr to avoid evaporation of the product. The product adsorbed onto silica gel was added to a column (diameter: ca. 7 cm, height: ca. 10-15 cm of a silica gel slurry in CH2CI2). About 300 mL CH2CI2 was passed through the column, and then the solvent was switched to 0.5% HCO2H in providing a dark brownsolution, which was partially concentrated using a rotary evaporator. To avoid losing the somewhat volatile cubane- 1,3 -diacid 4, following evaporation of the the residualformic acid was removed via azeotropic evaporation with pentane (ca. 7 x 5 mL) using a rotary evaporator. Afterwards, the mixture was transferred to an oven-dried 40 mL vial with MeOH, concentrated again, and briefly (for ca. 30 seconds) submitted to a high vacuum (ca. 0.5 ton). The brown solid or oil was then taken on to the esterification step with no purification.

[0210] The crude cubane- 1,3 -diacid 4 and cesium carbonate (1.43 g, 4.4 mmol, 10 equiv.) were suspended in dry DMF (4.4 mL, 1 M) and degassed for 10 min before methyl iodide (274 pL) was added and the reaction was stirred at 40 °C for 24 h. The solution was transferred into a separating funnel with Et2O (30 mL). 10% aqueous LiCl was added (25 mL). The phases were separated, and the aqueous phase was extracted with EtaO (5 x 25 mL). The combined organic phases were back extracted with 10% aqueous LiCl (1 x 20 mL), dried overNa2SO4, and concentrated. The crude product adsorbed on silica gel was purified by automatic column chromatography (gradient 100% hexane to 100% EtOAc, IS CO, visualization of the products by an ELS detector or 210 nm light) yielding dimethyl cubane- 1,3-dicarboxylate 4a as a white solid in 35% over the previous 4 steps (starting from the dihydropyridazine). NMR (400 MHz, CDCL) 8 4.46 (ddd, J = 6.0, 3.0, 1.8 Hz, 2H), 4.22 (tt, J = 4.9, 2.4 Hz, 2H), 4.08-3.92 (m, 2H), 3.71 (s, 6H);13C NMR (126 MHz, CDCh) 3 171.78, 53.39, 51.82, 51.23, 49.99, 42.97. ESI-MS: calculated [Ci2Hi2O4+Na]+: 243.0628, found: 243.0629. IRv = 3000.1, 2984.3, 2952.5, 1716.7, 1435.6, 1309.2, 1206.9, 1171.1, 1157.3, 1086.6, 1043.9, 1015.8, 907.2, 884.9, 854.0, 841.1, 802.2, 709.6.Example 8: Synthesis of Cubane Triester 9 by C-H Carboxylation

[0211] Twenty 40 mL vials were used for this synthesis. Into each 40 mL vial was added dimethyl cubane- 1,4-dicarboxylate 8 (220 mg, 1.0 mmol, 1.0 equiv.) and MeCN (20 mL, 0.05 M). The vials were degassed with N2 for 10 min, before degassed oxalyl chloride (0.12 mL, 1.5 equiv.) was added to each vial. The resulting vials were irradiated in an integrated photoreactor (365 nm, 100% light intensity, 5200 rpm fans, 500 rpm stirring) for 2 h. Pyridine (0.12 mL, 1.5 equiv.) and terLbutanol (1.9 mL, 20 equiv.) were added to each vial, and the resulting mixtures were stirred for 16 h. The reaction vials were then combined, before being diluted with H2O, and extracted with CH2CI2. The organics were dried (MgSCL), concentrated, and purified by automatic column chromatography using a 40 g Isco RediSep Rf gold column (eluent: gradient from 0 to 40% Et2O in hexane) to provide 2-(tert-butyl)-l,4-dimethyl cubane- 1, 2, 4-tricarboxylate 9 in a 51% yield as a white solid. NMR (500 MHz, CDCh) 5 4.40 (dt, J- 4.4, 1.9 Hz, 2H), 4.30-3.94 (m, 3H), 3.71 (s, 6H), 1.45 (s, 9H);13C NMR (126 MHz, CDCh) 5 171.20, 169.87, 168.30, 81.41, 58.08, 56.31, 53.45, 51.93, 51.76, 49.23, 47.71, 45.05, 28.19. ELMS: calculated [Ci7H2o06]+: 320.1254 found: 320.1242. IRv = 2980, 2953, 1720, 1435, 1393, 1368, 1323, 1216, 1154, 1119, 1090, 1011, 918, 842, 792, 730, 648, 457.Example 9: Synthesis of Cubane Monoacid 10

[0212] Six 40 mL vials were used for this synthesis. 2-(Tert-butyl)-l,4-dimethyl cubane- 1,2,4- tricarboxylate 9 (320 mg, 1.0 mmol, 1.0 equiv.) was added to each vial and placed under an N2 atmosphere. THF and MeOH (1 :1, 10 mL, 0.1 M) were added, followed by NaOH (1.0 equiv., 0.5mL, 2 M in H2O) dropwise at 0 °C. The reactions were allowed to warm up to room temperature and stirred for 24 h, before the vials were combined, diluted with water, acidified with 1 M aqueous KHSO4, and then extracted with EtOAc. The combined organics were dried (NaSO4), concentrated, and purified by automatic column chromatography using a 40 g Isco RediSep Rf gold column (eluent: gradient from 0 to 10% methanol in dichloromethane + 1% AcOH) to provide cubane monoacid 10 in a 59% yield as a white solid.rH NMR (500 MHz, CDCI3) 8 4.47 (dd, J = 4.5, 2.4 Hz, 2H), 4.30-4.18 (m, 3H), 3.74 (s, 3H), 1.47 (s, 9H);13C NMR (126 MHz, CDCI3) 8 175.21, 169.78, 168.28, 81.63, 58.08, 56.32, 53.05, 51.83, 49.20, 47.73, 45.10, 28.18. ESI-MS: calculated [Ci6Hi8O6+Na]+: 329.0996 found: 329.1008. IRv = 2991, 2954, 2927, 2850, 1713, 1677, 1632, 1510, 1478, 1459, 1428, 1410, 1367, 1321, 1301, 1260, 1225, 1184, 1154, 1123, 1087, 1069, 1042, 997, 940, 873, 843, 783, 766, 751, 709, 664, 642, 565, 492, 483, 468.Example 10: Synthesis of Cubane Diester 11

[0213] Step 1: The cubane monoacid 10 (894 mg, 2.92 mmol, 1.0 equiv.), EDC (558 mg, 1.1 equiv.), N-hydroxyphthalimide (573 mg, 1.1 equiv.), and DMAP (70.0 mg, ca. 20 mol%) were taken up in dry CH2C12(37 mL, 0.08 M) in a 40 mL oven-dried vial under an N2atmosphere at room temperature. The reaction was stirred for 16 h, before being diluted with CH2CI2, washed with water, and subsequently saturated aqueous NallCOs. The organics were dried (MgSCfi), concentrated, and purified by automatic column chromatography using a 40 g Isco RediSep Rf gold column (eluent: gradient from 0 to 20% EtOAc in hexane) to provide cubane SI in a 92% yield as a white solid.JH

[0214] Step 2: Cubane SI (589 mg, 1.3 mmol, 1.0 equiv.) and [Ir(ppy)2(dtbbpy)]PF6 (11.9 mg, 1 mol%) were added to an oven-dried 40 mL vial equipped with a stir bar and placed under an N2 atmosphere. Dry, degassed DMA (26 mL, 0.05 M) was added, followed by triethylamine (0.359 mL, 2.0 equiv.) and then 1,4-cyclohexadiene (0.244 mL, 2.0 equiv.). The vial was sealed with parafilm and placed inside the integrated photoreactor (450 nm, 25% light intensity, 5200 rpm fans, 500 rpm stirring). The reaction was stirred for 6 h, before being diluted with water, and extracted with Et2O. The organics were dried (MgSCM), concentrated onto silica, and purified by automatic column chromatography using a 40 g Isco RediSep Rf gold column (eluent: gradient from 0 to 100% EtOAc in hexane) to provide cubane diester 11 in a 75% yield as a white solid.3H NMR (500 MHz, CDCh) 5 4.25-4.15 (m, 4H), 4.05-3.85 (m, 2H), 3.70 (s, 3H), 1.43 (s, 9H);13C NMR (126 MHz, CDCI3) 5 170.69, 169.62, 80.76, 58.64, 57.75, 51.58, 47.45, 47.23, 45.55, 45.38, 28.22. EI-MS: calculated [CI5HI8O4]+: 262.1200 found: 262.1213. IRv = 2997, 2950, 2932, 1709, 1478, 1451, 1428, 1429, 1391, 1367, 1308, 1257, 1220, 1202, 1190, 1156, 1086, 1038, 1015, 988, 951, 909, 866, 844, 806,757, 723, 688, 633, 470, 427.ExaMe0

[0215] A 250 mL round-bottom flask was charged with iodomesitylene diacetate (0.146 mg, 0.4 mmol), 4-(methoxycarbonyl)cubane-l -carboxylic acid 16 (0.164 mg, 0.8 mmol, 2.0 equiv.), and 50 mL toluene. The flask was attached to a rotary evaporator with the water bath heated to 50 °C and the solvent (and the generated acetic acid) was removed over ca. 10 min. A second 50 mL aliquot oftoluene was added to the flask and the evaporation was repeated. The evaporation was repeated two more times. After further removal of residual toluene under high vacuum, lodomesitylene bis(4- (methoxycarbonyl)cubane-l -carboxylate) was directly used in the following amination reactions.

[0216] lodomesitylene bis(4-(methoxycarbonyl)cubane-l -carboxylate) (263 mg, 0.4 mmol, 1.0 equiv.), the nitrogen nucleophile (0.8 mmol, 2.0 equiv.), [Ir(dFMeppy)2(dtbbpy)]PF6 (7.1 mg, 1.75 mol%), and Cu(acac)2(52.4 mg, 50 mol%), were added to an oven-dried 40 mL vial equipped with a stir bar and placed under an N2atmosphere. Degassed 1,4-dioxane (12 mL, 0.33 M) was added followed by DBU (0.180 mL, 3.0 equiv.) and the vial was placed inside the integrated photoreactor (450 nm, 25% light intensity, 5200 rpm fans, 500 rpm stirring, single vial holder, 60 min). The reaction was concentrated and purified via automatic column chromatography using a 40 g Isco RediSep Rf gold column (eluent: gradient from 0 to 100% EtOAc in hexane).

[0217] Compounds 18-29, S2, and S3 were synthesized according to Example 11 using appropriate reagents and intermediates.CDCh) 8 7.75 (d, J= 8.8 Hz, 2H), 7.15 (s, 1H), 6.94 (d, J= 8.8 Hz, 2H), 4.52 (dd, J = 5.8, 4.5 Hz, 3H), 4.37 (q, J = 7.1 Hz, 2H), 4.27 (dd, J = 5.7, 4.5 Hz, 3H), 3.84 (s, 3H), 3.74 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H);13C NMR (126 MHz, CDCI3) 8 172.75, 159.62, 159.36, 149.87, 133.30, 126.82, 125.23, 114.11, 108.54, 73.07, 61.15, 55.33, 55.20, 51.65, 51.31, 44.98, 14.36. ESI-MS: calculated [C23H22N2O5+H]+: 407.1601, found: 407.1615. IR v = 2997, 2357, 1713, 1463, 1243, 1108, 837.

[0222] 22, 68% yield, white solid. 'll NMR (500 MHz, CDCh) 8 7.70 (s,2H), 4.62-4.49 (m, 3H), 4.38-4.26 (m, 3H), 3.74 (s, 3H);13C NMR (126 MHz, CDCh) 8 172.19, 134.91, 73.16, 56.41, 51.86, 50.97, 45.17. ESI-MS: calculated [C12H11N3O2W 230.0924, found: 230.0937. IRv = 3005, 2355, 1711, 1447, 1261, 957, 835.separations were required to yield a pure product. *H NMR (400 MHz, CDCh) 8 7.36 (d, J = 9.6 Hz, 1H), 7.18-7.11 (m, 2H), 6.48 (dd, J - 3.1, 0.9 Hz, 1H), 4.54^.48 (m, 3H), 4.39^4.32 (m, 3H), 3.77 (s, 3H);13C NMR (126 MHz, CDCh) 8 172.23, 153.41 (d, J = 238.3 Hz), 131.16, 128.47 (d, J = 9.0 Hz), 127.00, 115.57 (d, J = 21.3 Hz), 111.73, 107.35 (d, J = 23.3 Hz), 102.00 (d, J = 4.5 Hz), 70.26, 56.15, 51.92, 50.28, 44.77;19F NMR (376 MHz, CDCh) 8 -126.41 (dd, J = 9.7, 6.1 Hz). ESI-MS:(s, 1H), 6.59 (d, J ~ 3.0 Hz, 1H), 4.53 (t, J = 4.8 Hz, 3H), 4.38 (t, J= 4.6 Hz, 3H), 3.76 (s, 3H), 2aromatic peaks missing due to line-broadening;13C NMR (126 MHz, CDCI3) 6 171.94, 139.81, 134.73, 129.38, 101.85, 70.27, 56.21, 51.94, 50.53, 44.89. 3 C missing. ESI-MS: calculated [Ci7Hi3BrN2O2+H]+: 357.0233, found: 357.0255. IR v = 2997, 1720, 1471, 1439, 1326, 1211, 894.

[0225] 25, 80% yield, off-white solid. ’H NMR (400 MHz, CDClg) 57.69 (dt, J = 8.1, 1.0 Hz, 1H), 7.42 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.32 (dt, J = 8.6, 0.9 Hz, 1H), 7.26-7.20 (m, 1H), 4.71-4.55 (m, 3H), 4.4M.27 (m, 3H), 3.75 (s, 3H);13C NMR (101 MHz, CDCI3) 5 172.27, 139.86, 133.94, 127.69, 122.16, 121.86, 120.25, 110.28, 71.58, 56.25, 51.84, 50.72, 45.18. ESI-MS: calculated [C17H13CIN2O2W: 313.0738, found: 313.0753. IRv = 2997, 2355, 1723, 1466, 1334, 1243, 743.

[0226] 26, 72% yield, white solid. NMR (500 MHz, CDCI3) 5 8.32(brs, 1H), 7.76 (brs, 1H), 7.54-7.34 (m, 2H), 4.80 (t, J= 5.0 Hz, 3H), 4.46 (t, J = 4.7 Hz, 3H), 3.77 (s, 3H);13C NMR (126 MHz, CDCI3) 6 172.01, 127.86, 124.10, 120.31, 109.96, 70.22, 56.46, 51.95, 50.84, 45.68, 2 C missing. ESI-MS: calculated [Ci6Hi3N3O2+H]+: 280.1081, found: 280.1095. IRv = 2999, 2355, 1724, 1325, 1124, 1119, 768.

[0227] 27, 70% yield, off-white solid. NMR (500 MHz, CDCI3) 68.95 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.14 (d, J - 7.8 Hz, 1H), 7.96 (d, J = 5.2 Hz, 1H), 7.56 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.31 (t, J= 7.5 Hz, 1H), 4.88 (t, J - 5.2 Hz, 3H), 4.48 (dd, J = 6.0, 4.5 Hz, 3H), 3.78 (s, 3H);13C NMR (126 MHz, CDCI3) 5 172.21, 140.72, 139.07, 136.37, 132.98, 129.69, 128.66, 122.16, 122.03, 120.39, 114.93, 111.37, 71.48, 55.70, 51.92, 51.53, 45.21. ESI-MS: calculated [C2iHi6N2O2+H]+: 329.1285, found: 329.1315. IRv = 2996, 1725, 1461, 1452, 1435, 1323, 1280, 1231, 1201, 1137, 1090.

[0228] 28, 51% yield, white solid.JH NMR (500 MHz, CDCb) 8 8.26(d, J = 1.9 Hz, 1H), 6.96 (d, J = 1.9 Hz, 1H), 4.69 (dd, J = 6.0, 4.4 Hz, 3H), 4.35 (dd, J = 6.0, 4.4 Hz, 3H), 3.72 (s, 3H), 1.39 (s, 6H);13C NMR (126 MHz, CDCb) 8 179.01, 172.01, 154.83, 143.62, 136.73, 119.12, 118.35, 67.78, 55.49, 51.77, 49.91, 45.49, 45.07, 22.60. ESI-MS: calculated [Ci9Hi7BrN2O3+H]+: 401.0495, found: 401.0502. IRv = 2988, 2355, 1720, 1585, 1459, 1156, 727.

[0229] 29, 59% yield, white solid. The reaction was run at 0.1 M concentration.3H NMR (400 MHz, CDCb) 5 7.38 (tt, J = 8.4, 6.3 Hz, 1H), 6.95 (t, J = 8.3 Hz, 2H), 6.58 (s, 1H), 4.24 (q, J - 4.2 Hz, 6H), 3.72 (s, 3H); 'H NMR (500 MHz, CDCb) 6 7.31 (tt, J= 8.4,

[0230]

[0231] E

[0232] Trifluoromethanesulfonic acid (7.33 mL, 12.5 g, 83.0 mmol, 1.05 equiv.) was added to a flame-dried 250 mL Schlenk flask containing anhydrous CH2CI2 (240 mL, 0.33 M) via a glass syringe. Dropwise addition of the supersilane (24.5 mL, 19.8 g, 79.4 mmol, 1.0 equiv.) at 0 °C was accompanied by evolution of H2 gas. The mixture was allowed to warm up to room temperature over the course of 1 h. Then N,N-diisopropylethylamine (19.4 mL, 14.4 g, 111 mmol, 1.4 equiv.) and tertbutyl-methyl amine (3.7 mL, 2.69 g, 30.9 mmol, 1.05 equiv.) were added slowly at 0 °C at the same time. The ice bath was removed, and the resulting solution was stirred for 16 h at room temperature. Then, the solvent was evaporated under an N2 atmosphere by bubbling N2 through the solution while stirring and opening the vial up to air. The residue was redissolved in dry pentane and filtered. The filtrate was concentrated again by bubbling N2 through the solution to yield an oil. Dry acetonitrile (20 mL) was added, and precipitation was induced by Bonification. The supernatant was taken out by syringe and filtered. This process was repeated (7x) and the remaining semi-solid was transferred with a large spatula and acetonitrile to a fritted funnel, crushed with a spatula, retransferred to a vial, and dried under high vacuum overnight yielding a sticky white solid. Yield:

[0233] The reaction was conducted according to a modified literature procedure (Sakai, H. A., Liu, W., Le, C. & MacMillan, D. W. C. Cross-Electrophile Coupling of Unactivated Alkyl Chlorides. J.Am. Chem. Soc. 142, 11691 11697 (2020)). Purification was conducted by rapid column chromatography (gradient CH2CI2 to 10% EtOAc in CH2CI2).

[0234] The silane AdNHSi(TMS)3 (0.075 mmol, 1.5 equiv.; Ad = adamantanyl), cubane ester 30 (17.6 mg, 0.05 mmol, 1.0 equiv.), alkyl bromide (22.4 mg, 0.075 mmol, 1.5 equiv.), NaOAc (8.2 mg, 0.1 mmol, 2.0 equiv.), copper catalyst (indicated amount), and photocatalyst (1 mol%) were added to an oven-dried 4 mL vial equipped with a stir bar. The vial was degassed for 5 min by sparging with N2 before degassed acetone (0.5 mL) was added to provide a reaction concentration of 0.1 M. The reaction vial was placed in an integrated photoreactor (450 nm, 100% light intensity, 5200 rpm fans, 500 rpm stirring, multi-vial holder). After the indicated reaction time, a 0.25 M stock solution of mesitylene was added (0.2 mL, 0.05 mmol, 1.0 equiv.) and the mixture was stirred vigorously for 2 min. A sample (ca. 0.4 mL) was taken out and filtered over celite into an NMR tube (eluent: CDCI3). The yields of the remaining cubane ester 30, the cubane carboxylic acid A, the methyl cubane carboxylate B and the amount of desired product S4 were measured by NMR spectroscopy vs mesitylene. As shown in Tables 1-6, the following reaction parameters were optimized: reaction time, photocatalyst, copper catalyst, copper catalyst loading (mol%), reaction concentration, and silane.Table 1. Screening of Reaction Time

[0235] The silane ffiuMeNSi(TMS)3 (47% pure, 213 mg, 0.3 mmol, 1.5 equiv.), and subsequently the cubane redox-active ester 30 (70.3 mg, 0.2 mmol, 1.0 equiv.), the indicated alkyl bromide(0.3 mmol, 1.5 equiv.), NaOAc (32.8 mg, 0.4 mmol, 2.0 equiv.), the indicated copper catalyst(indicated amount), and 4-CzIPN (1.6 mg, 1 mol%) were added to an oven-dried 8 mL vial equipped with a stir bar. The vial was degassed for 5 min by sparging with N2 before a sufficient amount of degassed acetone was added to provide the reaction concentration as shown in Table 7. The reaction vial was placed in an integrated photoreactor (450 nm, 100% light intensity, 5200 rpm fans, 500 rpm stirring, single vial holder). After the indicated reaction time, a 1 M stock solution of mesityl ene was added (0.2 mL, 0.2 mmol, 1.0 equiv.) and the mixture was stirred vigorously for 2 min. A sample(ca. 0.4 mL) was taken out and filtered over celite into an NMR tube (eluent: CDCL). The yield of the desired product was measured by NMR spectroscopy vs mesitylene. The following parameters were optimized: copper catalyst, copper catalyst loading (mol%), and reaction concentration.

[0236] The silane tBuMeNSi(TMS)3 (47% pure, 213 mg, 0.3 mmol, 1.5 equiv.), the cubane redoxactive ester 30 (70.3 mg, 0.2 mmol, 1.0 equiv.), the indicated primary alkyl bromide (0.3 mmol, 1.5 equiv., if a solid, but if a liquid then the alkyl bromide is added with the acetone) NaOAc (32.8 mg,0.4 mmol, 2.0 equiv.), Cu(acac)2(5.2 mg, 10 mol%), and 4-CzIPN (1.6 mg, 1 mol%) were added to an oven-dried 8 mL vial equipped with a stir bar. The vial was degassed for 5 min by sparging withN2followed by the addition of degassed acetone (2 mL, 0.1 M) and the indicated primary alkyl bromide (0.3 mmol, 1.5 equiv., if a liquid). The reaction vial was placed in an integrated photoreactor (450 nm, 100% light intensity, 5200 rpm fans, 500 rpm stirring, single-vial holder, 30 min). Subsequently, the suspension was filtered over celite (eluent: EtOAc), concentrated, andpurified by automatic column chromatography using a 40 g Isco RediSep Rf gold column (eluent: gradient from 0 to 100% EtOAc in hexane).

[0237] Compounds 33-35, S4, and S5 were synthesized according to Example 16 with appropriate reagents and intermediates.

[0243] The silane fBuMeNSi(TMS)3 (47% pure, 213 mg, 0.3 mmol, 1.5 equiv.), and subsequently the cubane redox-active ester 30 (70.3 mg, 0.2 mmol, 1.0 equiv.), the indicated secondary alkyl bromide (0.3 mmol, 1.5 equiv., if a solid, but if a liquid then the alkyl bromide is added with the acetone), NaOAc (32.8 mg, 0.4 mmol, 2.0 equiv.), Cu(DMH)2(10.6 mg, 20 mol%), and 4-CzIPN (1.6 mg, 1 mol%) were added to an oven-dried 8 mL vial equipped with a stir bar. The vial was degassed for 5 min by sparging with N2followed by the addition of degassed acetone (4 mL, 0.05 M) and the indicated secondary alkyl bromide (0.3 mmol, 1.5 equiv., if a liquid). The reaction vialwas placed in an integrated photoreactor (450 nm, 100% light intensity, 5200 rpm fans, 500 rpm stirring, single-vial holder, 30 min). Subsequently, the suspension was filtered over celite (eluent: EtOAc), concentrated, and purified by automatic column chromatography using a 40 g Isco RediSep Rf gold column (eluent: gradient from 0 to 100% EtOAc in hexane).

[0244] Compounds 36-38 were synthesized according to Example 17 with appropriate reagents and intermediates.

[0245] , 48% yield, yellowish oil. NMR (300 MHz, CDCh) 8 7.43-7.29 (m, 5H), 5.13 (s, 2H), 4.10 (t, J= 5.0 Hz, 3H), 3.77 (t, J= 5.0 Hz, 3H), 3.70 (s, 3H), 3.62-3.42 (m, 2H), 3.43-3.29 (m, 1H), 3.05 (dt, J = 20.5, 9.5 Hz, 1H), 2.55- 2.40 (m, 1H), 1.97-1.82 (m, 1H), 1.74-1.48 (m, 1H);13C NMR (126 MHz, CDCI3) 8 172.76, 155.06 (d, J = 2.9 Hz), 137.08, 128.60 (d, J = 4.1 Hz), 128.15 (d, J = 6.0 Hz), 128.01 (d, J = 7.9 Hz), 66.89 (d, J = 9.5 Hz), 59.77 (d, / = 13.2 Hz), 56.66 (d, J = 3.6 Hz), 51.65, 46.77 (d, 64.6 Hz), 46.21 (d, J = 47.7 Hz), 46.13, 44.95,40.42 (d, J= 122.3 Hz), 25.98 (d, J = 100.6 Hz). ESI-MS: calculated [C22H23NO4+H]+: 366.1700, found: 366.1703. IRv = 2973.6, 2877.7, 1699.1, 1416.3, 1316.4, 1206.7, 1085.3, 840.6, 732.1, 697.0.

[0246] , 51% yield, off-white solid.!H NMR (500 MHz,CDCI3) 5 8.75 (d, J = 2.1 Hz, 1H), 7.93 (dd, J- 8.0, 2.1 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 4.91- 4.72 (m, 1H), 4.09 (t, J = 4.9 Hz, 3H), 3.81 (t, J = 4.9 Hz, 3H), 3.74-3.64 (m, 4H), 3.16-3.02 (m, 1H), 2.77 (t, J = 12.2 Hz, 1H), 1.87-1.71 (m, 2H), 1.70-1.57 (m, 1H);13C NMR (126 MHz, CDCh) 8 172.82, 166.37, 148.95 (q, J = 34.8 Hz), 148.11, 136.46, 134.99, 121.22 (q, J = 274.0 Hz), 120.55 (q, J = 2.8 Hz), 61.94, 56.46, 51.68, 46.15, 45.24 (brd J = 685.8 Hz), 44.14, 37.69, 25.74 (brd J = 145.28 Hz);19F NMR (376 MHz, CDCI3) 3 -68.14. ESI-MS: calculated [C22H2iN2O3+H]+: 419.1577, found: 419.1588. IRv = 2978.4, 2942.2, 2864.6, 1717.2, 1624.1, 1452.6, 1173.7, 1134.6, 1081.6,997.8, 839.7, 611.3.

[0247] 38, 52% yield, white solid. NMR (500 MHz, CDCI3) 8 7.09 (dd, J= 8.4, 5.4 Hz, 2H), 6.98 (t, J= 8.6 Hz, 2H), 4.01 (t, J= 4.9 Hz, 3H), 3.78 (t, J = 5.0 Hz, 3H), 3.69 (s, 3H), 2.95 (q, 7 - 7.0 Hz, 1H), 1.20 (d, J - 7.1 Hz, 3H);13C NMR (126 MHz, CDCI3) 8 172.96, 161.52 (d, 7 = 243.5 Hz), 138.94 (d, 7= 3.4 Hz), 128.59 (d, 7 = 7.6 Hz), 115.19 (d, 7= 21.0 Hz), 63.08, 56.42, 51.62, 45.80, 44.93, 40.50, 14.86;19F NMR (376 MHz, CDCI3) 8 -117.32. ESI-MS: calculated [CI8HI7O2F+H]+: 285.1285, found: 285.1285. IRv = 2978.6, 2960.3, 2852.7, 1723.9, 1601.90, 1505.7, 1437.6, 1325.7, 1209.5, 1156.6, 1086.3, 1039.6, 823.3, 730.3, 515.5.

[0248] DIG (1.6 mL, 1.0 equiv.) was added dropwise to a rapidly stirred suspension of the cubane carboxylic acid 16 (2.11 g, 10.3 mmol, 1.0 equiv.), tetrachloro-N-hydroxyphthalimide (3.23 g, 10.9 mmol, 1.05 equiv.), and DMAP (125 mg, 1.03 mmol, 10 mol%) in dry CH2CI2 (20 mL, 0.2 M) in a 100 mL oven-dried Schlenk flask under an N2atmosphere at room temperature. The reaction was stirred for 8 h, before being filtered over a celite pad (3 cm diameter and 3 cm height) with CH2C12as eluent (ca. 200 mL). The filtrate was concentrated using a rotary evaporator with the water bath set to 30 °C to yield the crude product as a yellow to orange solid. The crude product was dissolved in minimal CH2CI2 and filtered rapidly over silica gel using a fritted funnel (ca. 8 cm diameter, bottom layer: 1 cm (height) sand, then ca. 10 cm of silica gel, then another 2 cm sand; the solids were suspended with CH2C12before the solution of crude product was added). Small amounts of an orange solid were not completely dissolved in the CH2C12and remained in the flask or on top of the sand layer. The product was eluted with 4 L CH2C12into 3 separate flasks (fraction 1 : 300 mL CH2CI2, fraction 2: 2.5 L, fraction 3: 1.2 L). Rapid filtration prevented decomposition of the activated ester while a large amount of silica gel was required to prevent coelution with a yellowimpurity. All flasks were concentrated using a rotary evaporator with the water bath set to 30 °C. Fraction 2 (occasionally also fraction 3) provided a white to slightly yellowish solid upon concentration. This solid was redissolved in minimal CH2CI2 (ca. 80 mL) and added underneath a layer of pentane (400 mL) using a syringe with an attached needle. The biphasic mixture was stored at -20 °C for 16 h. After that time, the flask was allowed to warm up to room temperature, and a white solid was obtained by filtration. The filtrate was concentrated, and recrystallization was repeated to yield a second pure fraction. The third fraction was generally impure. Yield: 4.34 g, 8.87 mmol, 87%.Example 19: Cross Coupling Arylation of Cubanes

[0249] The silane )BuMeNSi(TMS)3 (1.5 equiv.), and subsequently cubane ester S6 (0.05 mmol, 1.0 equiv.), NaOAc (8.2 mg, 0.1 mmol, 2.0 equiv.), the Cu(acac)2 (indicated amount), and the photocatalyst (indicated amount) were added to an oven-dried 4 mL vial equipped with a stir bar. The vial was degassed for 5 min before degassed acetone (0.5 mL, 0.1 M) was added followed by the substrate (indicated amount). The reaction vial was placed in an integrated photoreactor (450 nm, 100% light intensity 5200 rpm fans, 1000 rpm stirring, multi-vial holder). After the indicated reaction time, a 0.25 M stock solution of the internal standards l-bromo-3,5- bis(trifluoromethyl)benzene and mesitylene was added (0.2 mL, 0.05 mmol, 1.0 equiv. each) and the mixture was stirred vigorously for 2 min. A sample (ca. 0.4 mL was taken out and filtered over celite into an NMR tube (eluent: CDCh). The yields of the remaining cubane ester S6, the hydrolyzed cubane carboxylic acid A, and the methyl cubane carboxylate B were measured by NMR spectroscopy vs mesitylene. The yields of the remaining aryl bromide, of the hydrodehalogenated arene, the aryl dimer, and of the desired product 40 were measured by19F NMR spectroscopy vs 1- bromo-3,5-bis(trifluoromethyl)benzene. The parameters silane purity, silane loading (equiv.), photocatalyst, photocatalyst loading (mol%), copper catalyst loading (mol%), and amount of aryl bromide (equiv.) were optimized.

[0250] The cross coupling arylation reactions were repeated and cubane ester S6 was replaced with the cubane ester 30. Results of the cross coupling arylation reactions with the cubane ester 30 is presented in Table 10Table 11. Photocatalyst screening with the cubane ester S6

[0251] BocaO (2.38 mL, 2.26 g, 10.4 mmol, 1.2 equiv.) was added portion wise to a stirred solution of IH-indazole (2 g, 8.64 mmol, 1.0 equiv.) and DMAP (52.8 mg, 0.432 mmol, 5 mol%) inMeCN (17.3 mL, 0.5 M) at room temperature leading to gas formation. After stirring for 16 h at room temperature, the solvent was evaporated under reduced pressure and the residue was partitioned between Et2O (100 mL) and H2O (100 mL). The aqueous phase was extracted with Et2O(3 x 100 mL). The organic layer was washed with a saturated aqueous NaHCOg solution (100 mL) and brine (100 mL) before being dried over anhydrous NagSOq. After filtration, the solvent was evaporated, and the crude product was purified by column chromatography (hexane / EtOAc) to give the desired product S7 as white solid. Yield: 2.75 g, 8.31 mmol, 96%. (II LMR (500 MHz, CDClg) 6 8.40 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.49 (dd, J = 8.5, 1.6 Hz, 1H), 1.71 (s, 9H);13C NMR (126 MHz, CDCh) 8 148.32, 141.38, 140.95, 128.08, 125.15, 122.48, 121.08, 118.25, 86.26, 28.20. ESIMS: calculated [Ci2Hi2BrClN2O2+Na]+: 354.9643, found: 354.9646. IRv = 2983.9, 1770.4, 1744.8, 1606.8, 1571.8, 1476.2, 1397.5, 1368.6, 1330.6, 1304.4, 1222.8, 1152.5, 1070.6, 984.9, 846.5, 807.9, 780.0, 752.8, 623.1, 583.7, 459.7.Example 21: Arylation of Cubanes - Aryl Halides

[0252] The silane(133.5 mg, 90% pure, 0.38 mmol, 1.8 equiv.), and subsequently the cubane ester S6 (97.8 mg, 0.2 mmol, 1.0 equiv.), NaOAc (32.8 mg, 0.4 mmol, 2.0 equiv.), the copper catalyst (indicated amount), and the substrate (3.0 equiv., if a solid, but if a liquid then the substrate is added after the addition of the acetone) were added to an oven-dried 8 mL vial equipped with a stir bar. The vial was degassed for 5 min before a 0.3 mM stock solution of [Ru(4,4’-dClbpy)3](PF6)2in degassed acetone (2.0 mL) was added followed by the substrate (3.0 equiv., if a liquid). Unless otherwise noted, two identical reactions were run in parallel, and placed inside the integrated photoreactor (450 nm, 100% light intensity, 5200 rpm fans, 1000 rpm stirring, multi-vial holder, 10 min). Both vials were combined and 40% KF on alumina (581 mg, 4 mmol) and tetra n-propylammonium bromide (266 mg, 1.00 mmol) were added and the suspension was stirred for 4 to 16 h. The suspension was filtered over celite (eluent: EtOAc), concentrated, and purified by automatic column chromatography using a 40 g Isco RediSep Rf gold column (eluent: gradient from 0 to 100% EtOAc in hexane).

[0253] Compounds 39-43 were synthesized according to Example 21 with appropriate reagents and intermediates.

[0254] 39, 47% yield, white solid. 15 mol% Cu(acac)2was used. No workup was conducted. Ca. 1% of a ring-opened isomeric product were inseparable from the reaction product. 'll NMR (500 MHz, CDCh) 8 7.63 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 4.28 (dd, J = 5.7, 4.0 Hz, 3H), 4.18 (t, J= 4.9 Hz, 3H), 3.74 (s, 3H);13C NMR (126 MHz, CDCh) 8 172.44, 147.49, 132.49, 125.74, 119.23, 109.85, 60.03, 56.58, 51.80, 48.93, 46.30. ESI-MS: calculated [Ci7Hi3NO2+Na]+: 286.0838, found: 286.0839. IR v = 2989.1, 2948.2, 2223.4, 1719.2, 1602.0, 1426.1, 1316.3, 1211.1, 1162.6, 1082.0, 857.9, 842.8, 552.9.

[0255] 40, 46% yield, white solid. 20 mol% Cu(acac)2was used. The reaction was run on a 0.4 mmol scale. Two subsequent chromatographic separations were required to yield a pure product. 'll NMR (500 MHz, CDCh) 8 7.60 (d, J = 8.0 Hz, 2H), 7.30 (d, .7 - 8.0 Hz, 2H), 4.28 (dd, J= 5.7, 4.1 Hz, 3H), 4.18 (dd, J = 5.7, 4.2 Hz, 3H), 3.74 (s, 3H);13C NMR (126 MHz, CDCh) 8 172.63, 146.10, 128.42 (q, J = 32.3 Hz), 124.49 (q, J = 272.2 Hz), 125.57 (q, J = 3.8 Hz), 125.28, 59.93, 56.59, 51.79, 48.88, 46.28;19F NMR (376 MHz, CDCh) 8 -62.30. ESI-MS: calculated [CI7HI3F3O2+H]+: 307.0940, found: 307.0947. IRv - 2986.6, 2923.9, 1727.0, 1611.2, 1438.1, 1318.1, 1212.8, 1153.4, 1115.1, 1092.0, 1066.9, 1012.6, 823.4, 673.5, 595.7.

[0256] 41, 48% yield, white solid. 15 mol% Cu(acac)2was used. 'HNMR (500 MHz, CDCh) 8 8.02 (dt, J= 8.2, 2.0 Hz, 2H), 7.26-7.22 (m, 2H), 4.36M.23 (m, 3H), 4.23-4.09 (m, 3H), 3.91 (s, 3H), 3.74 (s, 3H);13C NMR (126 MHz, CDCh) 8 172.68, 167.16, 147.40, 129.99, 128.00, 124.92, 60.20, 56.55, 52.20, 51.77, 48.96, 46.30. ESI-MS: calculated [CISHI6O4+H]+: 297.1121, found: 297.1124. IRv = 2951.8, 1708.8, 1603.3, 1431.7, 1317.6, 1277.0, 1217.3, 1086.7, 821.8, 763.1, 704.0.

[0257] 42, 46% yield, white solid. 20 mol% Cu(acac)2was used. The reaction was run on a 0.4 mmol scale. 0.5 mol% of [Ru(4,4’-dClbpy)3](PF6)2was used. The product was washed with small amounts of pentane after column chromatography to completely remove

[0258] yield, white solid. 25 mol% Cu(acac)2was used. The reaction was run 8 times on a 0.05 mmol scale at a 0.4 M concentration. The product was isolated alongside 0.11 equiv. of a ring-opened bisalkene-containing isomer of the desired product. TheExample 22: Arylation of Cubanes - Heteroaryl Halides

[0259] The silane fBuMeNSi(TMS)3(133.5 mg, 90% pure, 0.38 mmol, 1.8 equiv.), and subsequently the cubane ester S6 (97.8 mg, 0.2 mmol, 1.0 equiv.), NaOAc (32.8 mg, 0.4 mmol, 2.0equiv.), the copper catalyst (indicated amount), the substrate (3.0 equiv., if a solid, but if a liquid then the substrate is added after the acetone), and [Ir(dFCF3ppy)2(4,4’-d(CF3)bpy]PF6 (6.8 mg, 3 mol%) were added to an oven-dried 8 mL vial equipped with a stir bar. The vial was degassed for 5 min before degassed acetone (2 mL, 0.1 M) was added followed by the substrate (3.0 equiv., if a liquid). Unless otherwise noted, two identical reactions were run in parallel, and placed inside the integrated photoreactor (450 run, 100% light intensity, 5200 rpm fans, 1000 rpm stirring, multi- vial holder). Both vials were combined and purified by automatic column chromatography using a 40 g Isco RediSep Rf gold column as indicated.

[0260] Compounds 44 to 46 were synthesized according to Example 22 with appropriate reagents and intermediates.

[0261] white solid. 30 mol% Cu(acac)2was used. Thereaction was run 8 times on a 0.05 mmol scale. All reactions were combined, methanol (1.6 mL) was added, and the mixture was stirred for 2 h before it was purified by column chromatography (toluene / acetone). NMR (500 MHz, CDC13) 5 7.95 (s, 1H), 7.66 (d, 7= 8.3 Hz, 1H), 7.24 (dd, J = 8.2, 1.3 Hz, 1H), 4.35-4.26 (m, 3H), 4.23 (dd, J = 5.7, 4.0 Hz, 3H), 3.75 (s, 3H), 1.72 (s, 9H);13C NMR (126 MHz, CDCI3) 5 172.65, 148.84, 145.25, 141.32, 141.10, 121.97, 121.89, 120.25, 111.00, 85.61, 60.71, 56.58, 51.80, 49.12, 46.27, 28.26. ESI-MS: calculated [C22H2iClN2O4+Na]+: 435.1082, found: 435.1087. IRv = 2974.3, 1720.8, 1614.1, 1473.7, 1387.1, 1315.7, 1321.28, 1207.5, 1148.6,1055.8, 841.4, 753.0.yield, off-white solid. 20 mol% Cu(acac)2was used.2.5 mol% of [Ir(dFCF3ppy)2(4,4’-d(CF3)bpy]PF6 were used. The crude product was dry-loaded onto silica gel prior to chromatographic separation to avoid coelution with an unidentified impurity.111 NMR (400 MHz, CDCI3) 5 8.56 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 1.4 Hz, 2H), 4.32 (dq, J = 4.2, 3.2 Hz, 3H), 4.25 (dq, J= 4.2, 3.2 Hz, 3H), 3.75 (s, 3H);13C NMR (101 MHz, CDCI3) 6 172.26, 147.26, 146.10 (q, J = 34.7 Hz), 140.62, 133.73, 121.81 (q, J = 273.8 Hz), 120.31 (q, 7 = 2.8 Hz), 57.81, 56.62, 51.82, 48.78, 46.54. ESI-MS: calculated [Ci6Hi2F3NO2*H]*: 308.0893, found: 308.0901. IRv = 2954.2, 1711.5, 1313.8, 1132.0, 1083.7, 840.6, 690.4.

[0263] off-white solid. 65 mol% Cu(acac)2 was used.The crude product was dry-loaded onto silica gel and purified by column chromatography with toluene / acetone. 'H NMR (500 MHz, de-acetone) 8 8.30 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.91 (dd, 7 = 8.3, 1.5 Hz, 1H), 7.73 (ddd, 7 = 8.4, 6.9, 1.5 Hz, 1H), 7.54 (ddd, 7 = 8.1, 6.8, 1.2 Hz, 1H), 7.48 (d, 7 = 8.5 Hz, 1H), 4.38 (dd, 7 = 5.6, 4.1 Hz, 3H), 4.35-4.19 (m, 3H), 3.70 (s, 3H); 13C NMR (126 MHz, de-acetone) 8 172.37, 161.92, 149.02, 137.33, 130.26, 129.84, 128.73, 127.73, 126.72, 119.20, 62.38, 57.36, 51.63, 48.99, 47.18. ESI-MS: calculated [CI9HI5NO2+H]+: 290.1176, found: 290.1180. IRv = 2993.5, 2943.7, 1720.8, 1596.1, 1435.5, 1354.5, 1215.2, 1168.0, 1085.0, 943.6, 820.6, 753.4, 619.3, 461.9.

[0264] 4-(Methoxycarbonyl)cubane-l -carboxylic acid 16 (5.1 mg, 0.025 mmol, 1.0 equiv.), bis(2,5-dimethylphenyl)(trifluoromethyl)sulfonium trifluoromethanesulfonate (indicated amount), copper catalyst (indicated amount), photocatalyst (3 mol%), and Na2COs (7.8 mg, 0.075 mmol, 3.0 equiv.) were added to an oven-dried 8 mL vial equipped with a stir bar and placed under an N2 atmosphere. Degassed DMSO (0.25 mL, 0.1 M) was added, and the vial was placed inside the integrated photoreactor (450 nm, indicated light intensity, 5200 rpm fans, 500 rpm stirring, multi- vial holder, 8 h). 1,4-difluorobenzene (1.0 equiv.) was added and the yield was measured by19F NMR spectroscopy vs 1,4-difluorobenzene. Reaction parameters were explored as shown in Tables 16 to 20.Table 16. Impact of the copper loading

[0265] 4-(Methoxycarbonyl)cubane-l -carboxylic acid 16 (10.3 mg, 0.05 mmol, 1.0 equiv.), (2,5- dimethylphenyl)(trifluoromethyl)sulfonium trifluoromethanesulfonate (23.0 mg, 0.05 mmol, 1.0 equiv.), Copper(I) thiophene-2-carboxylate (1.2 mg, 12.5 mol%), [Ir(dFCF3ppy)2(5,5’-(CF3)bpy)]PF6 (1.7 mg, 3 mol%) and Na2COa (15.6 mg, 0.15 mmol, 3.0 equiv.) were added to an oven-dried 8 mL vial equipped with a stir bar and placed under an N2 atmosphere. Degassed DMSO(0.5 mL, 0.1 M) was added, and the vial was placed inside the integrated photoreactor (450 nm, 50% light intensity, 5200 rpm fans, 500 rpm stirring, multi-vial holder, 4 h). After 1 h and again after 2 h, additional bis(2,5-dimethylphenyl)(trifluoromethyl)sulfonium trifluoromethanesulfonate (23.0 mg,0.05 mmol, 1.0 equiv.) in degassed DMSO (0.5 mL) were added and the irradiation was continued.The reaction was run 4 times on a 0.05 mmol scale and an average19F NMR yield was measured vs1,4-difluorobenzene. The combined reaction mixtures were purified by automatic column chromatography using a 24 g Isco RediSep Rf gold column (eluent: gradient from 0 to 50% EtaO in hexane) to afford a yellow, volatile solid.

[0267] A I M solution of ammonium hydroxide in methanol (4.48 mL, 4.48 mmol, 1.1 equiv.) was added dropwise over 5 min to a solution of the cubane diester 4 (896 mg, 4.07 mmol, 1.0 equiv.) in dry MeOH (40 mL) at 0 °C under an N2 atmosphere. The mixture was stirred at 0 °C for 3 h before being allowed to warm up to room temperature. Following stirring at that temperature for 7 d, the solution was diluted with H2O (ca. 100 mL). NaCl (3 g) was added, and the solution was neutralized with 1 M KHSO4 (5 mL) and immediately extracted with EtOAc (8 x 70 mL). The combined organic extracts were concentrated using a rotary evaporator before being purified by column chromatography to provide 3-methoxycarbonylcubanecarboxylic acid 54 (CH2CI2 to 0.25% MeCO2H in 90:10 CH2Cl2 / MeOH). Yield: 588.1 mg, 2.85 mmol, 70%. NMR (500 MHz, deacetone) 8 4.39 (dt, J = 4.8, 2.4 Hz, 2H), 4.27-4.16 (m, 2H), 3.99 (q, J = 5.0 Hz, 2H), 3.66 (s, 3H); 13C NMR (126 MHz, de-acetone) 8 171.17, 170.72, 53.33, 53.20, 50.88, 50.79, 49.75, 49.72, 42.45. ESI-MS: calculated [CnHio04+Na]+: 229.0471, found: 229.0466. IRv = 3003.1, 2988.8, 1721.3, 1670.2, 1418.8, 1301.0, 1214.8, 1129.8, 998.9, 697.5, 474.0, 440.5.Example 26: Synthesis of 2-methoxycarbonvIcubanecarboxylic acid S8

[0268] TFA (8 mL, 53 equiv.) was added dropwise to a stirring solution of 1 -(tert-butyl) 2-methyl- cubane-l,2-dicarboxylate 11 (525 mg, 2.0 mmol, 1.0 equiv.) in dry CH2CI2 (34 mL, 0.06 M) under an N2 atmosphere. The resulting solution was stirred at room temperature for 16 h and then concentrated. The oil was dissolved in EtiO (2 mL), hexane was added (7 mL), the solution was

[0269] A 250 mL round-bottom flask was charged with iodomesitylene diacetate (0.146 mg, 0.4 mmol), 3 -(methoxycarbonyl)cubane-l -carboxylic acid 54 (0.164 mg, 0.8 mmol, 2.0 equiv.), and 50 mL toluene (0.008 M). The flask was attached to a rotary evaporator with the water bath heated to 50 °C and the solvent (and the generated acetic acid) was removed over ca. 10 min. A second 50 mL aliquot of toluene was added to the flask and the evaporation was repeated. The evaporation was repeated two more times. After further removal of residual toluene under high vacuum, hexane was added to the viscous oil and the suspension was sonicated followed by removal of the hexane to provide iodomesitylene bis(4-(methoxycarbonyl)cubane-l -carboxylate) as a solid, which was directly used in the following amination reactions.

[0270] lodomesitylene bis(3-(methoxycarbonyl)cubane-l -carboxylate) (131.3 mg, 0.2 mmol, 1.0 equiv.), 3 -chloroindazole (0.4 mmol, 2.0 equiv.), Cu(acac)2 (26.2 mg, 0.1 mmol, 50 mol%), and [Ir(dFMeppy)2(dtbbpy)]PF6 (3.6 mg, 1.75 mol%) were added to an oven-dried 40 mL vial equipped with a stir bar and placed under anN2 atmosphere. Degassed 1,4-dioxane (6 mL, 0.033 M) was added followed by DBU (0.09 mL, 3.0 equiv.) and the vial was placed inside the integrated photoreactor (450 nm, 25% light intensity, 1500 rpm fans, 500 rpm stirring, single-vial holder, 60 min). The reactions were concentrated and purified by automatic column chromatography using a 24 g Isco RediSep Rf gold column (eluent: gradient from 0 to 100% EtOAc in hexane).

[0271] 48, 72% yield, white solid. NMR (500 MHz, CDCh) 7.68 (dt,Example 28: Amination of 1,2-Cubane Isomers

[0272] To a 50 mL round-bottom flask was added iodosomesitylene (0.105 g, 0.4 mmol, 1.0 equiv.), 2-(methoxycarbonyl)cubane-l -carboxylic acid (88, 0.164 mg, 0.8 mmol, 2.0 equiv.), and CH2CI2 (4 mL, 0.1 M). The mixture was sonicated until it became homogenous, typically resulting in a slightly cloudy solution due to the liberation of water. Magnesium sulfate (0.144 g, 1.2 mmol, 3.0 equiv.) was added, and the reaction was stirred at room temperature for 30 min. The suspension was filtered, and the filtrate was concentrated in vacuo to provide iodomesitylene bis(4- methoxycarbonyl)cubane-l -carboxylate), which was directly used in the following amination reaction.

[0273] lodomesitylene bis(2-(methoxycarbonyl)cubane-l -carboxylate) (16.4 mg, 0.025 mmol, 1.0 equiv.), ethyl 3 -(4-methoxyphenyl)-pyrazole-5 -carboxylate (12.3 mg, 0.05 mmol, 2.0 equiv.), Cu(acac)2(4.9 mg, 0.019 mmol, 75 mol%), and [Ir(dFMeppy)2(dtbbpy)]PF6 (0.5 mg, 1.75 mol%), were added to an oven-dried 8 mL vial equipped with a stir bar and placed under anN2atmosphere. Degassed 1,4-dioxane (0.5 mL, 0.05 M) was added followed by DBU (11.2 pL, 3.0 equiv.) and the vial was placed inside the integrated photoreactor (450 nm, 65% light intensity, 1500 rpm fans, 500 rpm stirring, multi-vial holder, 60 min). The reaction was run 4 times, the reaction mixtures were combined, concentrated, and purified by reversed phase (Cl 8) chromatography (eluent: gradient from 0 to 100% H2O in MeCN with 0.1% NH4OH).

[0274] 7.77 (d, J = 8.8 Hz, 2H), 7.14 (s, IH), 6.94 (d, J = 8.8 Hz, 2H), 4.66-4.64 (m, 2H), 4.38- 4.21 (m, 4H), 3.98 (dtq, J = 12.6, 4.9, 2.4 Hz, 2H), 3.84 (s, 3H), 3.52 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H);13C NMR (126 MHz, CDCI3) 8 170.50, 159.80, 159.68, 150.05, 134.05, 127.02, 125.52, 114.15, 108.39, 73.83, 62.30, 61.28, 55.45, 51.45, 51.40, 45.87, 45.22, 43.16, 14.45. ESI-MS: calculated [C23H22N2O5+Na]+: 429.1421, found: 429.1451. IRv = 2998, 2355, 1720, 1558, 1446, 1286, 1246, 1106, 767.Example 29: Synthesis of Cuban e Ester S90. o1.0 equiv. EDC, 10 mol% DMAP MeO2'oO [0.1 M] in THE, 25 °C, 8 h54 S9

[0275] EDC (0.288 g, 1 equiv.), cubane carboxylic acid 54 (0.309 g, 1.50 mmol, 1.0 equiv.), N- hydroxyphthalimide (0.256 g, 1.05 equiv.), and DMAP (18.4 mg, 10 mol%) were taken up in dry THE (15 mL, 0.1 M) in a 40 mL oven-dried vial under anN2atmosphere at room temperature. The reaction was stirred for 8 h, before being concentrated, and purified by automatic column chromatography using a 24 g Isco RediSep Rf gold column (eluent: gradient from 0 to 10% EtOAc in CH2C12). S9, 82% yield, white solid. *H NMR (500 MHz, CDC13) § 7.90 (dd, J = 5.4, 3.1 Hz, 2H), 7.80 (dd, J = 5.5, 3.1 Hz, 2H), 4.71 (dt, J = 4.7, 2.4 Hz, 2H), 4.47 (dq, J = 5.1, 2.5 Hz, 1H), 4.26 (dq, J= 5.0, 2.5 Hz, 1H), 4.13 (q, J = 5.0 Hz, 2H), 3.74 (s, 3H).Example 30: Cross Coupling Alkylation of 1,3-Cubanes

[0276] The silane tBuMeNSi(TMS)3 (110.2 mg, 90% pure, 0.3 mmol, 1.8 equiv.), the cubane redox-active ester S9 (70.3 mg, 0.2 mmol, 1.0 equiv.), NaOAc (54.4 mg, 0.4 mmol, 2.0 equiv.), Cu(acac)2(10.5 mg, 20 mol%), (4-bromopiperidin-l-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (101.1 mg, 0.3 mmol, 1.5 equiv.), and 4-CzIPN (1.6 mg, 1 mol%), were added to an oven-dried 40 mL vial equipped with a stir bar and placed under an N2atmosphere. Degassed acetone (4.0 mL, 0.05 M) was added, and the vial was placed inside the integrated photoreactor (450 nm, 100% light intensity, 1500 rpm fans, 500 rpm stirring, single vial holder, 30 min). The reaction was concentrated and purified by automatic column chromatography using a 24 g Isco RediSep Rf gold column (eluent: gradient from 0 to 100% EtOAc in hexane).

[0277] CDCb) 5 8.74 (s, 1H), 7.92 (dd, J = 7.9, 2.1 Hz, 1H), 7.74 (d, ,7 - 8.0 Hz, 1H), 4.81 (d, J = 13.1 Hz, 1H), 4.25 (dq, J = 5.0, 2.5 Hz, 1H), 4.14-3.96 (m, 2H), 3.87-3.77 (m, 3H), 3.68 (s, 4H), 3.19-3.01 (m, 1H), 2.76 (t, J = 12.9 Hz, 1H), 1.87-1.73 (m, 2H), 1.61 (d, J - 13.2 Hz, 1H), 1.36-1.21 (m, 1H), 1.20-1.04 (m, 1H);13C NMR (126 MHz, CDCb) 5 172.69, 166.33, 148.88 (q, J= 35.1 Hz), 148.10, 136.46, 134.97, 121.28 (q, J = 274.4 Hz), 120.54 (d, J = 2.9 Hz), 59.13, 52.51, 51.67, 50.20, 48.58 (d, J = 5.5 Hz), 46.72, 45.19 (brd, J = 686.8 Hz), 41.69, 37.36, 25.61 (brd, J= 142.8 Hz);19F NMR (376 MHz, CDCb) 6 -68.14. ESI-MS: calculated [C22H2iF3N2O3+Na]+: 441.1396, found: 441.1411; IRv = 2985, 2354, 1668, 1332, 1137, 731.Example 31: Synthesis of Cubane Ester S10

[0278] EDC (0.230 g, 1 equiv.), cubane carboxylic acid S8 (0.247 g, 1.20 mmol, 1.0 equiv.), N- hydroxyphthalimide (0.205 g, 1.05 equiv.), and DMAP (14.7 mg, 10 mol%) were taken up in dry THF (12 mL, 0.1 M) in an oven-dried vial 40 mL under an N2 atmosphere at room temperature. The reaction was stirred for 8 h, before being concentrated and purified by automatic column chromatography using a 24 g Isco RediSep Rf gold column (eluent: gradient from 0 to 10% EtOAc in CH2C12). S10, 86% yield, white solid.1H NMR (500 MHz, CDC13) 8 7.88 (dd, J= 5.5, 3.1 Hz, 2H), 7.78 (dd, J = 5.5, 3.1 Hz, 2H), 4.49 (td, J = 5.0, 2.3 Hz, 2H), 4.38 (td, J = 4.9, 2.3 Hz, 2H), 4.11 (qt, J - 4.9, 2.3 Hz, 1H), 4.02 (qt, J = 4.8, 2.2 Hz, 1H), 3.82 (s, 3H);13C NMR (126 MHz, CDCI3) 8 169.68, 165.66, 161.91, 134.84, 129.12, 124.07, 58.38, 55.05, 52.29, 47.97, 47.93, 46.40, 45.53. ESI-MS: calculated [Ci9Hi3NO5+Na]+: 374.0635 found: 374.0632; IR v - 2998, 2357, 1742, 1725, 1220, 902, 695.

[0279] The silane / BuMcNSi(TMS)3 (13.8 mg, 90% pure, 0.0375 mmol, 1.5 equiv.), cubane redoxactive ester S10 (8.8 mg, 0.025 mmol, 1.0 equiv.), NaOAc (6.8 mg, 0.05 mmol, 2.0 equiv.), Cu(acac)2 (0.3 mg, 5 mol%), 7-(4-bromobutoxy)-3,4-dihydroquinolin-2-one (11.2 mg, 0.0375 mmol, 1.5 equiv.), and 4-CzIPN (0.2 mg, 1 mol%), were added to an oven-dried 8 mL vial equipped with a stir bar and placed under anlSh atmosphere. Degassed acetone (0.25 mL, 0.1 M) was added, and the vial was placed inside the integrated photoreactor (450 nm, 30% light intensity, 1500 rpm fans, 500 rpm stirring, multi- vial holder, 15 min). The reaction was repeated 4 times and an average NMR yield was recorded with respect to 1,3,5-trimethoxybenzene. The product was purified usingreversed phase (Cl 8) chromatography (eluent: gradient from 0 to 100% H2O in MeCN with 0.1% NH4OH).

[0280] , white solid. 'll NMR (500 MHz, CDCI3) 8 7.66 (s, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.51 (dd, J = 8.3, 2.4 Hz, 1H), 6.29 (d, J = 2.5 Hz, 1H), 4.11 (td, J =54 S11

[0281] DIC (0.423 mL, 1.0 equiv.) was added dropwise to a rapidly stirred suspension of the cubane carboxylic acid 54 (0.563 g, 2.73 mmol, 1.0 equiv.), tetrachloro-N-hydroxyphthalimide (0.862 g, 1.05 equiv.), and DMAP (33.4 mg, 10 mol%) in dry CH2CI2 (14 mL, 0.2 M) in an oven- dried 40 mL vial under an N2atmosphere at room temperature. The reaction was stirred for 8 h, before being concentrated using a rotary evaporator with the water bath set to 30 °C. The crude product was dissolved in minimal CH2CI2 and passed rapidly through a short silica gel column (eluent: CH2C12). Sil, 90% yield, white solid. ’H NMR (500 MHz, CDC13) 5 4.70 (dt, J = 4.8, 2.4 Hz, 2H), 4.47 (tq, J - 4.9, 2.3 Hz, 1H), 4.27 (tq, J = 4.8, 2.3 Hz, 1H), 4.14 (q, J = 4.9 Hz, 2H), 3.74 (s, 3H);13C NMR (126 MHz, CDCh) 8 171.00, 166.25, 157.76, 141.20, 130.63, 124.89, 52.01, 51.60, 50.55, 50.02, 43.73. ESI-MS: calculated [Ci9H9C14NO6+Na]+: 509.9076, found: 509.9105. IR v = 3001, 2355, 1743, 1377, 1215, 1153, 753.

[0282] The silane tBuMeNSi(TMS)3 (16.5 mg, 90% pure, 0.045 mmol, 1.8 equiv.), cubane redoxactive ester Sil (12.2 mg, 0.025 mmol, 1.0 equiv.), NaOAc (6.8 mg, 0.05 mmol, 2.0 equiv.), Cu(acac)2(1.3 mg, 20 mol%), 4-bromobenzonitrile (13.7 mg, 0.075 mmol, 3.0 equiv.), and [Ru(4,4*- dClbpy)3](PF6)2 (0.5 mg, 2 mol%), were added to an oven-dried 8 mL vial equipped with a stir bar and placed under an N2 atmosphere. Degassed acetone (0.25 mL, 0.1 M) was added, and the vial was placed inside the integrated photoreactor (450 nm, 40% light intensity, 1500 rpm fans, 500 rpm stirring, multi-vial holder, 15 min). The reaction was run 4 times, on a 0.025 mmol scale and the reaction mixtures were combined, concentrated, and purified by automatic column chromatography using a 12 g Isco RediSep Rf gold column (eluent: gradient from 0 to 100% EtOAc in hexane).

[0284] DIG (0.081 mL, 1.0 equiv.) was added dropwise to a rapidly stirred suspension of cubane carboxylic acid S8 (0.163 g, 0.79 mmol, 1.0 equiv.), tetrachloro -N-hydroxyphthalimide (0.2496 g, 1.05 equiv.), and DMAP (9.7 mg, 10 mol%) in dry CH2CI2 (4 mL, 0.2 M) in an oven-dried 40 mLvial under an N2 atmosphere at room temperature. The reaction was stirred for 8 h, before being concentrated using a rotary evaporator with the water bath set to 30 °C. The crude product was dissolved in minimal CH2CI2 and passed rapidly through a short silica gel column (eluent: CH2O2). S12, 82% yield, white solid. 'H NMR (500 MHz, CDCh) 8 4.48 (td, J = 4.9, 2.2 Hz, 2H), 4.38 (td, J - 4.9, 2.3 Hz, 2H), 4.12 (qt, J = 4.9, 2.3 Hz, 1H), 4.02 (qt, J = 4.9, 2.2 Hz, 1H), 3.82 (s, 3H);13C NMR (126 MHz, CDCI3) 8 169.53, 165.23, 157.52, 141.11, 130.57, 124.88, 58.34, 54.77, 52.36, 48.03, 47.94, 46.48, 45.58. ESI-MS: calculated [Ci9H9C14NO6+Na]+: 509.9076, found: 509.9084. IR v = 3001, 2356, 1745, 1723, 1377, 1196, 724.Example 36: Cross Coupling Arylation of 1,2-Cubanes

[0285] The silane fBuMeNSi(TMS)3 (16.5 mg, 90% pure, 0.045 mmol, 1.8 equiv.), the cubane redox-active ester S12 (12.2 mg, 0.025 mmol, 1.0 equiv.), NaOAc (6.8 mg, 0.05 mmol, 2.0 equiv.), Cu(acac)2 (0.7 mg, 10 mol%), 2-bromo-6-(trifluoromethyl)pyridine (16.9 mg, 0.075 mmol, 3.0 equiv.), and [Ir(dFCF3ppy)(4,4’-d(CF3)bpy)]PF6 (0.72 mg, 2.5 mol%), were added to an oven-dried 8 mL vial equipped with a stir bar and placed under an N2 atmosphere. Degassed acetone (0.25 mF, 0.1 M) was added, and the vial was placed inside the integrated photoreactor (450 nm, 40% light intensity, 5200 rpm fans, 500 rpm stirring, multi-vial holder, 15 min). The reaction was run 4 times on a 0.025 mmol scale and the reaction mixtures were combined, concentrated, and purified by automatic column chromatography using a 12 g Isco RediSep Rf gold column.

[0286] 53, 18% yield, white solid. NMR (500 MHz, CDCh) 8 7.80 (t, J = 7.8 Hz, 1H), 7.47 (dd, J - 7.7, 1.0 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 4.34 (tt, J = 5.7, 2.8 Hz, 4H), 4.05 (dddd, J = 20.5, 7.4, 4.9, 2.5 Hz, 2H), 3.57 (s, 3H);13C NMR (126 MHz, CDCh) 8 171.15, 159.77, 147.92 (q, J = 34.3 Hz), 137.45, 122.77, 121.64 (q, J = 274.3 Hz), 117.88 (q, J= 2.9 Hz), 62.51, 59.29, 51.42, 48.78, 46.87, 45.98, 44.91;19F NMR (376 MHz, CDCh) 6 -68.01. ESI-MS:calculated [Ci6Hi2F3NO2+Na]+: 330.0712, found: 330.0717. IRv = 2996, 2357, 1722, 1466, 1358, 1139, 1120.

[0287] A 250 mL round-bottom flask was charged with iodomesitylene diacetate (0.146 mg, 0.4 mmol), 4-(methoxycarbonyl)cubane-l -carboxylic acid 16 (0.164 mg, 0.8 mmol, 2.0 equiv.), and 50 mL toluene. The flask was attached to a rotary evaporator with the water bath heated to 50 °C and the solvent (and the generated acetic acid) was removed over ca. 10 min. A second 50 mL aliquot of toluene was added to the flask and the evaporation was repeated. The evaporation was repeated two more times. After further removal of residual toluene under high vacuum, lodomesitylene bis(4- (methoxycarbonyl)cubane-l-carboxylate) was directly used in the following amination reaction.

[0288] lodomesitylene bis(4-(methoxycarbonyl)cubane-l -carboxylate) (262.6 mg, 0.4 mmol, 1.0 equiv.), the nitrogen nucleophile (0.8 mmol, 2.0 equiv.), [Ir(dFMeppy)2(dtbbpy)]PFe (7.1 mg, 1.75 mol%), and Cu(acac)2(52.4 mg, 50 mol%), were added to an oven-dried 40 mL vial equipped with a stir bar and placed under anN2atmosphere. Degassed 1,4-dioxane (12 mL, 0.33 M) was added followed by DBU (0.180 mL, 3.0 equiv.) and the vial was placed inside the integrated photoreactor (450 nm, 25% light intensity, 5200 rpm fans, 500 rpm stirring, single vial holder, 60 min). The reaction was concentrated and purified by automatic column chromatography using a 40 g Isco Redi Sep Rf gold column (eluent: gradient from 0 to 100% EtOAc in hexane).Equivalents

[0292] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.Incorporation by Reference

[0293] All publications, patents, and patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A process for the preparation of cubane- 1,3 -dicarboxylic acid :comprising the steps of:1) an endocyclic photocyclization of a protected dihydropyridazine to form a protected diazetidine;2) deprotection and oxidation of the diazetidine to diazine followed by nitrogen extrusion to provide cyclobutadiene;3) a Diels-Alder cycloaddition of the cyclobutadiene with a quinone substituted with at least two leaving groups to form a bisalkene;4) a light-mediated internal [2+2] cycloaddition of the bisalkene to form a cyclic diketone or its monohydrate; and5) a Favorskii ring contraction of the diketone or its monohydrate to provide cubane-1,3- dicarboxylic acid2. The process of claim 1, wherein the bisalkene is of the formula:, wherein X and Y are the leaving groups.

3. The process of claim 2, wherein the cyclic diketone is of the formula:, wherein X and Y are the leaving groups.

4. The process of claim 1, wherein the endocyclic photocyclization of dihydropyridazine comprises irradiation of dihydropyridazine in a suitable solvent.

5. The process of claim 4, wherein the irradiation of dihydropyridazine comprises irradiating dihydropyridazine in dichloromethane with light at a wavelength of about 365 nm.

6. The process of any one of claims 1-5, wherein the electrophilic transcarbamation of the Boc- protected diazetidine comprises treating the Boc-protected diazetidine with trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,6-lutidine in dichloromethane.

7. The process of any one of claims 1-6, wherein the oxidation is performed with 2,5- dibromoquinone.

8. The process of any one of claims 1-7, wherein the light-mediated internal [2+2] cycloaddition comprises irradiating bisalkene in toluene with light at a wavelength of about 450 nm.

9. The process of any one of claims 1-8, wherein the Favorskii ring contraction of the diketone or its monohydrate comprises treating the diketone or its monohydrate with potassium hydroxide in water.

10. A process for the preparation of dialkyl cubane-l,2-dicarboxylate esters of Formula (I): wherein R1is alkyl; and R comprising:1) a light-mediated C-H carboxylation and esterification sequence of dialkyl cubane-1,4- dicarboxylate of Formula (la): wherein R1is alkyl; andto provide a trialkyl cubane-l,2,4-tricarboxylate ester of Formula (II):Formula (II); wherein R1is alkyl; R2is alkyl; and R3is alkyl;2) a regioselective deprotection of the -CO2R3group of Formula (II) to provide the monoacid of Formula (III):and3) a decarboxylation of the carboxylic acid of the monoacid of Formula (III).

11. The process of claim 10, wherein the light-mediated C-H carboxylation comprises adding oxalyl chloride to dialkyl cubane-l,4-dicarboxylate in a suitable solvent and irradiating the reaction at a suitable wavelength.

12. The process of claim 11, wherein the suitable wavelength is about 280 nm to about 600 nm.

13. The process of claim 12, wherein the suitable solvent is acetonitrile and the irradiation is performed for about 0.5 hours to about 4 hours.

14. The process of any one of claims 10-13, wherein the esterification comprises adding a suitable alcohol and a suitable base after the irradiation is completed.

15. The process of claim 14, wherein the suitable alcohol is methanol, ethanol, isopropanol, or tert-butanol; and the suitable base is pyridine or lutidine.

16. The process of any one of claims 10-15, wherein the regioselective deprotection of the trialkyl cubane-l,2,4-tricarboxylate of Formula (II) is performed with sodium hydroxide, potassium hydroxide, or lithium hydroxide in a suitable solvent.

17. The process of claim 16, wherein the suitable solvent is water, methanol, ethanol, tetrahydrofuran, ethyl acetate, tetrahydrofuran, or a combination thereof.

18. The process of any one of claims 10-17, wherein the regioselective deprotection of step 2 is neutralized with a suitable acid.

19. The process of claim 18, wherein the suitable acid is acetic acid, citric acid, oxalic acid, lactic acid, hydrochloric acid, sulfuric acid, or potassium hydrogen sulfate.

20. The process of any one of claims 10-19, wherein the decarboxylation comprises transforming the carboxylic acid of Formula (III) to a redox-active ester and performing a photoredox- mediated decarboxylation.

21. The process of claim 20, wherein the redox-active ester is -C(=O)-O-N-succinimidyl, -C(=O)-O-N-phthalimidyl, -C(=O)-O-N-tetrachlorophthalimidyl, -C(=O)-OBt, -C(=O)-Oat, or -C(=O)-O-N- 1 ,8-naphthalimidyl.

22. The process of claim 20 or 21, wherein the photoredox-mediated decarboxylation comprises mixing the redox-active ester of the carboxylic acid of Formula (III), a suitable photocatalyst,a suitable hydrogen atom donor, and a suitable base, in a suitable solvent, and irradiating the mixture at a suitable wavelength.

23. The process of claim 22, wherein the suitable hydrogen atom donor is 1 ,4-cyclohexadiene, substituted or unsubstituted aryl thiol, or substituted or unsubstituted alkyl thiol.

24. The process of claim 22 or 23, wherein the suitable wavelength is about 280 nm to about 600 nm.

25. The process of any one of claims 22-24, wherein the suitable photocatalyst is Eosin Y, 1,2, 3, 5- tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4-CzIPN), 2,4,5,6-tetrakis(9H-carbazol-26. The process of any one of claims 22-25, wherein the suitable base is triethylamine and the suitable solvent is dimethylacetamide (DMA).

27. A compound having the following structure:wherein R1is alkyl; and R2is alkyl.

28. The compound of claim 27, wherein:R1is methyl, ethyl, propyl, Ao-propyl, n-butyl, Ao-butyl, sec-butyl, or t-butyl; and R2is methyl, ethyl, propyl, Ao-propyl, u-butyl, Ao-butyl, sec-butyl, or / -butyl.

29. The compound of claim 27, wherein the compound has the following structure:

30. A compound having the following structure:wherein,Rlais H, -C(=O)OR1, -R5, or -CH(R6)(R7);Rlbis H, -C(=O)OR2, -R5, or -CH(R6)(R7);Rlcis H, -C(=O)OR1, -R5, or -CH(R6)(R7);Rldis H, -C(=O)OR2, -R5, or -CH(R6)(R7); each R1is independently H or C1-C6alkyl; each R2is independently H or C1-C6alkyl;R4is a redox-active ester; each R3is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, alkylene-(substituted or unsubstituted cycloalkyl), alkylene-(substituted or unsubstituted heterocycloalkyl), alkylenesubstituted or unsubstituted aryl), or - alkylene-(substituted or unsubstituted heteroaryl); each of R6and R7is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, - alkylene-(substituted or unsubstituted cycloalkyl), - alkylene-(substituted or unsubstituted heterocycloalkyl), - alkylene-(substituted or unsubstituted aryl), or - alkylene-(substituted or unsubstituted heteroaryl); or R6and R7are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl.

31. The compound of claim 30, wherein the compound has one of the following structures:wherein,Rlais -C(=O)OR1, -R5, or -CH(R6)(R7);Rlbis -C(=O)OR2, -R5, or -CH(R6)(R7);Rlcis -C(=O)OR1, -R5, or -CH(R6)(R7); and32.R4is aN-hydroxy-phthalimide ester, N-hydroxy-tetrachlorophthalimide ester, thiohydroxamate ester, l-hydroxy-7-azabenzotriazole (HOAt) ester, hydroxybenzotriazole (HOBt) ester, or iodomesityl ene ester.

33. The compound of claim 30 or 31, wherein:

34. The compound of claim 30, wherein the compound has one of the following structures:

35. A process for the amination, alkylation, trifluoromethylation, arylation, or heteroarylation of a compound of Formula (IV):wherein,R10is a redox-active ester or -C(=O)OH;Rnis H or -C(=O)OR1;R12is H or -C(=O)OR1;R15is H or -C(=O)OR1; and each R1is independently C1-C6alkyl, provided at least one of R11, R12, and Rbis not H, comprising a copper catalyzed or mediated decarboxylative amination, copper catalyzed or mediated decarboxylative alkylation, copper catalyzed or mediated decarboxylative trifluoromethylation, copper catalyzed or mediated decarboxylative arylation, or copper catalyzed or mediated decarboxylative heteroarylation of the compound of Formula (IV) in the presence of a substituted or unsubstituted heteroaryl comprising a NH, an amide comprising a NH, a substituted or unsubstituted alkyl halide, or an electrophilictrifluoromethylation reagent a substituted or unsubstituted aryl halide, a substituted or unsubstituted heteroaryl halide.

36. The process of claim 35, wherein the decarboxylative amination of the cubane-carboxylic acid comprises reacting the cubane-carboxylic acid with a cyclic or acyclic hypervalent iodine (III) reagent, followed by the addition of a suitable photocatalyst, a suitable copper catalyst, a suitable base, a suitable solvent, a substituted or unsubstituted heteroaryl comprising a NH or an amide comprising a NH, and irradiation at suitable wavelength.

37. The process of claim 36, wherein the cyclic or acyclic hypervalent iodine (III) reagent is benziodoxole (Bl)-alkoxyl (BIOR), benziodoxole (Bl)-hydroxyl (BIOH), benziodoxole (BI)- acetate (BIO Ac), or iodomesitylene diacetate (MesI(Oac)2).

38. The process of claims 36 or 37, wherein the suitable base is an organic base or inorganic base.

39. The process of any one of claims 36-38, wherein the suitable base is triethylamine, diisopropylethylamine, sec-butylamine, 1,2,2,6,6-pentamethylpiperidine, tributylamine, or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

40. The process of any one of claims 36-39, wherein the suitable solvent is 1,4-dioxane.

41. The process of any one of claims 36-40, wherein the substituted or unsubstituted 5-10 membered heteroaryl comprising a NH comprises a substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted triazole, substituted or unsubstituted tetrazole, substituted or unsubstituted pyrrole, substituted or unsubstituted indole, substituted or unsubstituted benzimidazole, substituted or unsubstituted indazole, substituted or unsubstituted azaindazole, substituted or unsubstituted isoindole, substituted or unsubstituted carbazole, substituted or unsubstituted P-Carboline, substituted or unsubstituted pinoline, substituted or unsubstituted ibogamine, or substituted or unsubstituted harmine.

42. The process of any one of claims 36-40, wherein the amide comprising aNH comprises a substituted or unsubstituted primary amide, substituted or unsubstituted secondary amide, or substituted or unsubstituted cyclic amide.

43. The process of claim 42, wherein the substituted or unsubstituted cyclic amide comprises a substituted or unsubstituted P-lactam, substituted or unsubstituted y-lactam, substituted or unsubstituted 5-lactam, or substituted or unsubstituted e-lactam.

44. The process of claim 42, wherein the substituted or unsubstituted cyclic amide comprises a substituted or unsubstituted 2-azetidinone, substituted or unsubstituted pyrrolidin-2-one, substituted or unsubstituted pyrrolidine -2, 5 -di one, substituted or unsubstituted piperidin-2-one, substituted or unsubstituted piperidin-2, 6-dione, substituted or unsubstituted azepan-2- one, substituted or unsubstituted indolin-2-one, substituted or unsubstituted isoindolin-l-one, substituted or unsubstituted isoindoline- 1,3 -dione, substituted or unsubstituted 3,4- dihydroisoquinolin-l(2H)-one, substituted or unsubstituted 3,4-dihydroquinolin-2(lH)-one, substituted or unsubstituted isoindo line- 1, 3 -dithione, substituted or unsubstituted benzo[d]oxazol-2(3H)-one, substituted or unsubstituted lH-benzo[d]imidazol-2(3H)-one, substituted or unsubstituted benzo[d]thiazol-2(3H)-one, substituted or unsubstituted phthalimide, substituted or unsubstituted cyclohexane-l,2-dicarboximide, or substituted or unsubstituted cyclopentane- 1 ,2-dicarboximide.

45. The process of claim 35, wherein the copper catalyzed or mediated decarboxylative alkylation comprises combining a cubane comprising a redox active ester, a substituted or unsubstituted C1-Cealkyl halide, a halogen atom abstractor, a suitable photocatalyst, a suitable copper catalyst, and irradiating the mixture at a suitable wavelength.

46. The process of claim 45, wherein the redox active ester is -C(=O)-O-N-succinimidyl, -C(=O)-O-N-phthalimidyl, -C(=O)-O-N-tetrachlorophthalimidyl, -C(=O)-OBt, -C(=O)-OAt, or -C(=O)-O-N-l,8-naphthalimidyl.

47. The process of any one of claims 45-46, wherein the halogen atom abstractor is a silane or a germane.

48. The process of any one of claims 45-47, wherein the halogen atom abstractor is a silane that comprises a Si-OH moiety, a Si-N bond, or a Si-O-N bond; or a germane that comprises a Ge-OH moiety, a Ge-N bond, or a Ge-O-N bond.

49. The process of any one of claims 45-48, wherein the halogen atom abstractor is tris(trimethylsilyl)silanol, N - tris(trimethy 1 si ly 1) si ly 1 adamantan- 1 -amine, N- tris(trimethylsilyl)silyl-tert-butylamine, N-methyl-N-tris(trimethylsilyl)silyl-tert-butylamine, N-tris(trimethylsilyl)silylmesitylamine, tris(trimethylsilyl)germanol, N- tris(trimethylsilyl)germanyladamantan- 1 -amine, N- tris(trimethylsilyl)germanyl-tert- butylamine, N-methyl-N-tris(trimethylsilyl)germanyl-tert-butylamine, or N- tris(trimethylsilyl)germanylmesitylamine.

50. The process of claim 35, wherein the copper catalyzed or mediated decarboxylative trifluoromethylation of a cubane comprising the oxidative decarboxylation of a cubane- carboxylic acid in the presence of an electrophilic trifluoromethylation reagent.

51. The process of claim 50, wherein: the electrophilic trifluoromethylation reagent is selected from:wherein each R13is independently -Me, -Et, -F, -Cl, -OMe, or -Ph; n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and each R14is independently substituted or unsubstituted C1-C4alkyl or substituted or unsubstituted C6-C10aryl.

52. The process of claim 50 or 51, wherein: oxidative decarboxylation of the cubane-carboxylic acid comprises combining the cubane- carboxylic acid with a suitable photocatalyst, a suitable copper catalyst, and a suitable base, and irradiating the mixture at a suitable wavelength.

53. The process of any one of claims 50-52, wherein the suitable base is an organic base or inorganic base.

54. The process of claim 35, wherein the cubane-carboxylic acid has the structure of Compound14: wherein R1is C1-C6alkyl.

55. The process of claim 35, wherein the copper catalyzed or mediated decarboxylative arylation, or copper catalyzed or mediated decarboxylative heteroarylation of a cubane comprises combining a cubane comprising a redox active ester, a substituted or unsubstituted aryl halide or substituted or unsubstituted heteroaryl halide, a halogen atom abstractor, a suitable photocatalyst, a suitable copper catalyst, a suitable base, and irradiating at a suitable wavelength.

56. The process of claim 55, wherein:the redox active ester is -C(=O)-O-N-succinimidyl, -C(^O)-O-N-phthalimidyl, -C(=O)-O-N- tetrachlorophthalimidyl, -C(=O)-OBt, -C(=O)-OAt, or -C(=O)-O-N-l,8-naphthalimidyl.

57. The process of claim 55 or 56, wherein the halogen atom abstractor is a silane or a germane.

58. The process of any one of claims 55-57, wherein the halogen atom abstractor is a silane comprises a Si-OH moiety, a Si-N bond, or a Si-O-N bond; or a germane that comprises a Ge-OH moiety, a Ge-N bond, or a Ge-O-N bond.

59. The process of any one of claims 55-58, wherein the halogen atom abstractor is tris(trimethylsilyl)silanol, N-tris(trimethylsilyl)silyladamantan-l -amine, N- tris(trimethylsilyl)silyl-tert-butylamine, N-methyl-N-tris(trimethylsilyl)silyl-tert-butylamine, N-tris(trimethylsilyl)silylmesitylamine, tris(trimethylsilyl)germanol, N- tris(trimethylsilyl)germanyladamantan- 1 -amine, N- tris(trimethylsilyl)germanyl-tert- butylamine, N-methyl-N-tris(trimethylsilyl)germanyl-tert-butylamine, or N- tris(trimethylsilyl)germanylmesitylamine.

60. The process of any one of claims 55-59, wherein the halide of the substituted or unsubstituted C6-C10aryl halide or substituted or unsubstituted 5-10 membered heteroaryl halide is Br or I.

61. The process of any one of claims 55-60, wherein the substituted or unsubstituted C6-C10aryl of the substituted or unsubstituted C6-C10aryl halide is a substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.

62. The process of any one of claims 55-60, wherein the substituted or unsubstituted 5-10 membered heteroaryl of the substituted or unsubstituted 5-10 membered heteroaryl halide is a substituted or unsubstituted pyridinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl, substituted or unsubstituted furazanyl, substituted or unsubstituted indolizine, substituted or unsubstituted indolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted benzofurazanyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstitutedindazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted purinyl, substituted or unsubstituted quinolizinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted cinnolinyl, substituted or unsubstituted phthalazinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted 1,8 -naphthyr idinyl, substituted or unsubstituted furopyridinyl, or substituted or unsubstituted pteridinyl.

63. The process of any one of claims 36-62, wherein the suitable photocatalyst is an organic photocatalyst, an organometallic photocatalyst, an inorganic photocatalyst, or an organic photocatalyst comprising a substituted or unsubstituted cyanobenzene.

64. The process of any one of claims 36-62, wherein: the suitable photocatalyst is Eosin Y, 1 ,2,3,5- tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4-65. The process of any one of claims 36-64, wherein the suitable copper catalyst is a copper (I) catalyst or copper (II) catalyst.

66. The process of any one of claims 36-65, wherein the suitable copper catalyst isCu(tBuCN)i-3X (X = OTf, BF4, or PF6), CuCl, CuBr, Cui, CuTc, CuCN, CuOAc, or CuOTf*l / 2C6H6.

67. The process of any one of claims 36-66, wherein the suitable wavelength is about 280 nm to about 600 nm.

68. A compound selected from:

69. A compound selected from:

70. A compound of formula (V):wherein R1is C1-Cg alkyl.

71. A compound selected from:

72. A compound selected from:Cl CO Me73. A compound of Formula (III): or a salt thereof, whereinR1is C1-C6alkyl; andR2is C1-C6alkyl.

74. A method of cubane alkylation or arylation comprising: forming a cubyl radical from a cubane redox active ester; forming an alkyl radical or aryl radical via halogen extraction from an alkyl halide or aryl halide;C-C cross coupling the cubyl radical with the alkyl radical or aryl radical with a copper catalyst.

75. The method of claim 74, wherein the cubyl radical is reductively generated via charge transfer from a transition metal catalyst.

76. The method of claim 75, wherein the transition metal catalyst is a photocatalyst.

77. The method of claim 76, wherein the photocatalyst generates a silyl radical for the halogen extraction from the alkyl halide or the aryl halide.

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