Templated deprotonative metalation of polyaryl systems: Facile access to simple, previously inaccessible multi-iodoarenes

Building blocks for pharmaceutical/electronic materials have been prepared using a templated C–H bond–breaking approach.


General methods and chemicals
All reactions and manipulations were performed under a protective atmosphere of dry pure argon gas using standard Schlenk techniques unless otherwise stated. n-Hexane was dried by heating to reflux over sodium benzophenone ketyl and used as freshly distilled under nitrogen atmosphere.
Methylcyclohexane was distilled over sodium metal under nitrogen and then stored with activated 4 Å molecular sieves under argon prior to use. Anhydrous N,N-dimethylformamide (DMF) was purchased from Aldrich and used without further purification. [D12]cyclohexane and [D6]benzene were degassed and stored over activated 4 Å molecular sieves under argon prior to use. 2,2,6,6-tetramethylpiperidine [TMP(H)] was purchased from Merck KGaA and stored over activated molecular sieves (4 Å). n BuLi (1.6M in hexanes) and n Bu2Mg (1M in heptane) solutions were purchased from Aldrich and titrated prior to use. Copper iodide, carbazole, potassium carbonate, 18-crown-6, anhydrous N,Ndimethylformamide, sodium thiosulfate, iodine, anhydrous magnesium sulfate, ammonium chloride and sodium chloride were purchased from Aldrich and used as received. n BuNa (50), NaTMP (51) and n BuMgTMP (29) were prepared according to literature methods and used as solids from a glove-box or in situ. Sodium tert-butoxide was purchased from Aldrich and dried under vacuum at 150ºC in an Schlenk tube for 30 min prior to use. Biphenyl, meta-terphenyl (1,3-diphenylbenzene), para-terphenyl (1,4-diphenylbenzene) and 1,3,5-triphenylbenzene were purchased from Aldrich and used without further purification. Biphenylene was prepared according to the reported method and used as a crystalline solid (4). n BuNa, NaTMP, n BuMgTMP and the organometallic products 2, 4, 6, 12 and 14 were isolated and handled inside an argon-filled glove-box whereas the derivatives 8 and 10 were in situ prepared and used as methylcyclohexane solutions. Organic products 3, 5, 7, 8, 9, 11, 13, 15, and 16 were isolated without the need of protocols to exclude atmospheric oxygen or moisture. NMR spectra were recorded on a Bruker DPX 400 MHz spectrometer, operating at 400.1 and 100.6 MHz for 1

Organometallic derivatives
Detailed synthetic protocols are given for each organometallic derivative. Notice that the organometallic derivatives 8 and 10 are highly soluble in commonly used hydrocarbons (e.g. methylcyclohexane, n-hexane and pentane) hampering their crystallization and isolation. However, the NMR spectroscopic analyses in [D12]cyclohexane for the in situ reaction mixtures that yield 8 and 10 in methylcyclohexane solution are in agreement with the proposed formulations. Therefore, the in situ preparation of 8 and 10, and their NMR characterization are included in this section. Each [Mg] empirically represents [Na2Mg(TMP)3] fragments in the formula diagrams for the organometallic compounds 2, 4, 6, 8, 10, 12 and 14.
Commercial n Bu2Mg (2 mL, 1M solution in n-heptane, 2 mmol) was then added via syringe to give a 0.05M pale yellow solution of [Na4Mg2(TMP)6( n Bu)2] 1 in methylcyclohexane. The metalating reagent 1 was stirred for 30 min at ambient temperature prior to use. Then, biphenyl (154 mg, 1 mmol) was added and the resulting reaction mixture was heated to 65°C for 16 h to give a pale brown suspension. NMR spectroscopic analyses of aliquots of the in situ reaction mixture are in agreement with the presence of 2 as the major organometallic species in solution. The pale brown suspension was left at ambient temperature for 24 h and then it was filtered using standard Schlenk techniques. The collected solid was washed with n-hexane (3 x 5 mL) and dried under vacuum for 20 min to give 2 as a pale brown solid (870 mg, 0.735 mmol, 74%). Crystals of 2 suitable for an X-ray diffraction study were obtained by reacting 1 (20 mL, 0.05 M solution in methylcyclohexane) with biphenyl (154 mg, 1 mmol) under reflux for 10 min and allowing the reaction mixture to slowly cool down to ambient temperature in a Dewar containing hot [Mg] [Mg] water (c.a. 80 °C) for a period of 48 h (823 mg, 0.695 mmol, 70%). The NMR spectra of the isolated pale brown solid and the crystalline material corresponding to that of 2 are coincident and appear to show that its X-ray structure is retained in [D12]cyclohexane solution.  Residual NMR spectroscopic signals for methylcyclohexane (C7H14), solvent of crystallization present in the crystal lattice of 2, are also present in the [D12]cyclohexane solutions of 2. Elemental analyses in combination with NMR spectroscopy reveal that the methylcyclohexane solvent of crystallization is only partially removed under vacuum during the isolation of 2. Isolated compound 2 exhibits low solubility in [D12]cyclohexane; however, it was fully characterized by 1 H and 13 C NMR spectroscopy.
Residual signals corresponding to biphenyl and TMP(H) are present within the [D12]cyclohexane solutions of 2 due to unavoidable hydrolysis and low solubility of crystalline 2 in [D12]cyclohexane.
Compound 4: [Na4Mg2(TMP)6(3,5-para-terphenyl-di-ide)] Preparation. In an argon-filled Schlenk tube, freshly prepared n BuNa (320 mg, 4 mmol) was suspended in methylcyclohexane (17 mL) and TMP(H) (1.02 mL, 6 mmol) was then added via syringe to produce NaTMP as a pale yellow suspension which was stirred for 30 min at room temperature. Commercial n Bu2Mg (2 mL, 1M solution in n-heptane, 2 mmol) was then added via syringe to give a 0.05M [Mg] [Mg] pale yellow solution of [Na4Mg2(TMP)6( n Bu)2] 1 in methylcyclohexane. The metalating reagent 1 was stirred for 30 min at ambient temperature prior to use it. Then, para-terphenyl (230.3 mg, 1 mmol) was added and the resulting reaction mixture was heated to 45°C for 48 h to give a light pale brown suspension. The pale brown suspension was left at ambient temperature for 24 h and then filtered used standard Schlenk techniques. The collected solid was washed with n-hexane (3 x 5 mL) and dried under vacuum for 20 min to give 4 as a pale brown solid (320 mg, 0.264 mmol, 26%). Several attempts to crystallize 4 were unsuccessful, yielding microcrystalline materials (c.a. 15-34%) not suitable for a single crystal X-ray diffraction study. heated to 65°C for 16 h to give a pale brown suspension. The pale brown suspension was filtered used standard Schlenk techniques. The collected solid was washed with n-hexane (3 x 5 mL) and dried under vacuum for 30 min to give 6 as a pale brown solid (1.23 g, 0.583 mmol, 59%). Crystals of 6 suitable for an X-ray diffraction study were obtained by mixing 1 (20 mL, 0.05 M solution in methylcyclohexane) with para-terphenyl (115.2 mg, 0.5 mmol), then heating the reaction mixture to reflux for 5 min until completely solubility of para-terphenyl and allowing the reaction mixture to slowly cool down to ambient temperature in a Dewar containing hot water (c.a. 80 °C) for a period of 48 h (710 mg, 0.334 mmol, 69%). The NMR spectra of isolated pale brown solid and crystals of 6 are coincident in [D12]cyclohexane solution.
Physical state: Pale brown solid, colorless plate crystals.  Preparation (in situ). In an argon-filled Schlenk tube, freshly prepared n BuNa (320 mg, 4 mmol) was suspended in methylcyclohexane (17 mL) and TMP(H) (1.02 mL, 6 mmol) was then added via syringe to give NaTMP as a pale yellow suspension which was stirred for 30 min at ambient temperature. Commercial n Bu2Mg (2 mL, 1M solution in n-heptane, 2 mmol) was then added via syringe to give a 0.05M pale yellow solution of [Na4Mg2(TMP)6( n Bu)2] 1 in methylcyclohexane. The metalating reagent 1 was stirred for 30 min at ambient temperature prior to use it. Then, metaterphenyl (230.3 mg, 1 mmol) was added and the resulting reaction mixture was heated at 45°C for 48 h to give a dark orange solution. The solvent was removed under vacuum to give an amber color oily  material. NMR spectroscopic analyses of aliquots of the in situ reaction mixture and the isolated oily material are in agreement with the presence of 8 as a major organometallic species in solution (c.a. 64% based on meta-terphenyl) along with unreacted meta-terphenyl and/or generated by unavoidable hydrolysis of 8. Several attempts to crystallize and isolate 8 were unsuccessful due to its high solubility in commonly used hydrocarbon solvents (methylcyclohexane, n-hexane, pentane); however, this in situ mixture of 8 can be used for electrophilic quenches without further purification. Compound 10 [Na8Mg4(TMP)12(3,3',5,3'-para-terphenyl-tetra-ide)] Preparation (in situ). In an argon-filled Schlenk tube, freshly prepared n BuNa (640 mg, 8 mmol) was suspended in methylcyclohexane (24 mL) and TMP(H) (2.04 mL, 12 mmol) was then added via syringe to produce NaTMP as a pale yellow suspension which was stirred for 30 min at room temperature. Commercial n Bu2Mg (4 mL, 1M solution in nheptane, 4 mmol) was then added via syringe to give a 0.067M pale yellow solution of [Na4Mg2(TMP)6( n Bu)2] 1 in methylcyclohexane. The metalating reagent 1 was stirred for 30 min at ambient temperature prior to use it. Then, meta-terphenyl (230.3 mg, 1 mmol) was added and the resulting reaction mixture was heated at 65°C for 16 h to give a dark orange solution. The solvent was removed under vacuum to give a dark amber color oily material. NMR spectroscopic analyses of an aliquots of the in situ reaction mixture and the isolated oily material are in agreement with the presence of 10 as major organometallic species in solution. Several attempts to crystallize and isolate 10 were unsuccessful due to its high solubility in methylcyclohexane; however, this in situ mixture of 10 can be used for electrophilic quenches without further purification.
The collected solid was washed with n-hexane (3 x 5 mL) and dried under vacuum for 30 min to give 12 as a brown solid (1.20 g, 0.507 mmol, 51%). Crystals of 12 suitable for an X-ray diffraction study were obtained by mixing 1 (40 mL, 0.05 M solution in methylcyclohexane) with 1,3,5-triphenylbenzene (230 mg, 0.75 mmol), then heating the reaction mixture to reflux and allowing the reaction mixture first to slowly cool down to ambient temperature in a Dewar containing hot water (c.a. 80 °C) and then allowing the reaction mixture to stand at room temperature for a week (0.93 g, 0.393 mmol, 52% based on 1,3,5-triphenylbenzene). The NMR spectra of the isolated pale brown solid and crystals of 12 are coincident in [D6]benzene solution.

Compound 14 [Na4Mg2(TMP)6(1,4-biphenylene-di-ide)]
Preparation. In an argon-filled Schlenk tube, freshly prepared n BuNa (640 mg, 4 mmol) was suspended in methylcyclohexane (24 mL) and TMP(H) (2.04 mL, 12 mmol) was then added via syringe to give NaTMP as a pale yellow suspension which was stirred for 30 min at room temperature. Commercial n Bu2Mg (4 mL, 1M solution in n-heptane, 4 mmol) was then added via syringe to give a 0.067M pale yellow solution of [Na4Mg2(TMP)6( n Bu)2] 1 in methylcyclohexane. The metalating reagent 1 was stirred for 30 min at ambient temperature prior to using it. Then, biphenylene (304 mg, 2 mmol) was added and the resulting reaction mixture was stirred at ambient temperature for 6 h to give a light orange-brown suspension. The suspension was filtered using standard Schlenk techniques. The collected solid was washed with n-hexane (3 x 5 mL) and dried under vacuum for 20 min to give 14 as a pale yellow solid (1.62 g, 1.343 mmol, 67% based on biphenylene). Crystals of 14 suitable for an X-ray diffraction study were obtained by mixing 1 (10 mL, 0.1 M solution in methylcyclohexane) with biphenylene (152 mg, 1 mmol), then heating the reaction mixture to reflux and allowing the reaction mixture to slowly cool down to ambient NMR spectroscopic analysis of an aliquot of the filtrate corresponding to the reaction mixture that gives 14 reveals the existence in solution of a second set of resonances, which mimicks the resonances of the isolated complex 14, and that correspond to a second conformer of 14 (see figs. S1 and S2 for full details). A 1:0.8 ratio between the major (isolated, less soluble in methylcyclohexane) and minor (soluble in methylcyclohexane) conformers of 14 is found in the filtrate. Similar conformers have been previously seen and fully studied in related ferrocenyl inverse crown derivatives. 43 Physical state: Pale yellow solid, pale yellow plate-like crystals.

Electrophilic quenches
General synthetic procedures. The corresponding organic substrate (biphenyl, para-terphenyl, meta-terphenyl, 1,3,5-triphenylbenzene and biphenylene; 1 mmol each) was treated with an in situ solution of 1 in methylcyclohexane prepared prepared according to the synthetic organometallic  (see table S1). After the in situ metalation step was achieved, the reaction mixture was cooled to -78 ºC in a dry ice/acetone bath for 30 mins and then added (either via cannula or disposable air-tight syringe) to an iodine solution in tetrahydrofuran (thf) at the same temperature. For the preparation of 3, 5, 9, and 15, 10 mL of a 1M solution of iodine in thf was used, whereas for 7, 11, and 13, 20 mL of a 1M solution of iodine in thf was employed. The resulting reaction mixtures were stirred at -78 ºC for at least 3 h and then allowed to slowly warm up to ambient temperature for a period of 24 h. Saturated aqueous NH4Cl solution (c.a. 10 mL) was then added, followed by saturated aqueous Na2S2O3 solution (c.a. 10 mL) until bleaching occurred. The crude mixture was extracted with EtOAc (3 x 20 mL) and the combined organic layers were washed with brine (20 mL) and dried over anhydrous MgSO4. The solvent was removed in a rotary evaporator and the crude product was purified by flash column chromatography (silica gel, nhexane/ethyl acetate) to yield the pure title compound. Alternatively, 7 can be prepared in 51% yield by reacting 6 (1 mmol) with an iodine/thf solution (20 mmol iodine/20 mL thf). The organic derivatives 3, 5, 7, 13 and 15 can be crystallized from either MeOH, EtOH and/or EtOAc. Compounds 7, 11 and 13 exhibit low solubility in commonly used organic solvents which hinders their isolation and purification in the scale used in their preparations.

Synthesis of 9,9'-(3,5-biphenyl)bis(carbazole) 16.
In an argon-filled Schlenk tube, 3,5-diiodo-1,1'biphenyl (150 mg, 0.37 mmol) was mixed with carbazole (140 mg, 0.83 mmol), potassium carbonate (114 mg, 0.83 mmol), copper(I) iodide (32 mg, 0.17 mmol) and 18-crown-6 (30 mg, 0.1 mmol). Then anhydrous N,N-dimethylformamide (DMF) was added (5 mL) and the reaction mixture was refluxed for 24 h under argon atmosphere. After cooling down to ambient temperature, the reaction mixture was filtered throught a short pad of Celite and the solvent was removed under vacuum. The crude product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate) to yield the pure title compound as a pale yellow solid. 16 can be crystallized from ethyl acetate by slow evaporation to give colorless block like crystals suitable for an X-ray diffraction study.  Additional details for 3: The phenyl C6H5 group was modeled as disordered over two sites with 50% occupancy each, and the geometries and displacement parameter of the disordered groups were allowed to freely refine.

X-ray crystal structure of 5 (CCDC 1516424)
Crystal data for 5: C18H12I2, M = 482.08 g/mol, monoclinic, C2/c, a = 18.1628 (8) Additional details for 5: The phenyl C6H5 and phenylene C6H4 groups were modeled as disordered over two sites with 50% occupancy each, and the geometries and displacement parameter of the disordered groups were allowed to freely refine.

X-ray crystal structure of 6 (CCDC 1516425)
Crystal data for 6: C126H226Mg4N12Na8, M = 2190.33 g/mol, monoclinic, C2/m, a = 15.8990 (14) Additional details for 6: One TMP ligand and the phenylene C6H4 group were modeled as disordered over two sites, and the geometries and displacement parameters of the disordered groups were restrained to approximate typical values. The SQUEEZE routine of PLATON-2016 (55) was used to remove the effects of residual electron density corresponding to disordered methylcyclohexane solvent molecules, which could not be satisfactorily modeled. Approximately 383 electron equivalents were removed from 1875 Å 3 of "void" space per unit cell. This corresponds to approximately seven methylcyclohexane solvent molecules per unit cell.

Alert level B
THETM01_ALERT_3_B The value of sine(theta_max)/wavelength is less than 0.575 Calculated sin(theta_max)/wavelength = 0.5722 Author Response: Structure 6 is a low angle dataset from a very weakly diffracting crystal. Despite much effort, no better dataset could be obtained. As is made clear in the main body of the paper, the low resolution structure is used only for purposes of atomic connectivity.

PLAT910_ALERT_3_B Missing # of FCF Reflection(s) Below Theta(Min) 20 Note
Author Response: These statistics are acceptable given the size of the molecule and of the unit cell.