Enantiospecific Syntheses of Congested Atropisomers through Chiral Bis(aryne) Synthetic Equivalents

Abstract The synthetic equivalents of the enantiopure binaphthyl bis(aryne) atropisomers derived from BINOL (1,1′‐bi‐2,2′‐naphtol) featuring a stereogenic axis vicinal to the two reactive triple bonds can be generated for the first time in solution in an enantiospecific manner. Using a two‐step sequence based on the bidirectional [4+2] cycloaddition of furan derivatives followed by an aromatizative deoxygenation reaction, several 9,9’‐bianthracenyl‐based atropisomers could be prepared enantiospecifically in high enantiomeric purity. Alternatively, bidirectional reactions with anthracene, 2‐bromostyrene, and perylene as the arynophiles afforded very congested bis(benzotriptycene), bis(tetraphene) and bis(anthra[1,2,3,4‐ghi]perylene) nanocarbon atropisomers in equally high enantiomeric purity. In complement, cross reactions with two different arynophiles revealed possible. The unusual atropisomer prototypes described in this study open the way to enantiopure nanographene atropisomers designed for functions.


General information
Reactions were generally carried out under an argon atmosphere in oven-dried reaction vessels in anhydrous solvents. All reagents were weighed and handled in air at room temperature unless otherwise mentioned, and all commercially available reagents were used as received unless otherwise mentioned. Anhydrous dichloromethane, diethyl ether, and toluene were dried by filtration over solid dehydrating agents using a commercial solvent purification system. Anhydrous acetonitrile was obtained directly from commercial sources. Thin layer chromatography was carried out on Merck Kieselgel 60 F254 0.2 mm plates. Visualization was accomplished using ultraviolet light (254 and/or 365 nm) and/or chemical staining with an ethanolic solution of para-anisaldehyde with sulphuric acid as appropriate. Purifications were routinely performed using flash chromatography columns packed with 40-63 μm silica gel generally eluted with a mixture pentane/ethyl acetate or pentane/diethyl ether.
Melting points were recorded using Büchi Melting Point B-540 or B-545 apparatus.
NMR data were generally recorded at 298 ± 3 K in deuterated chloroform at 400 MHz or 500 MHz using as internal standards the residual chloroform signal for 1 H NMR (δ = 7.26 ppm) and the deuterated solvent signal for 13 C NMR (δ = 77.16 ppm). Chemical shifts (δ) are in ppm, coupling constants (J) are in Hertz (Hz) and the classical abbreviations are used to describe the signal multiplicities. 13 C DEPT135 experiments were systematically conducted to support assignments.
Optical Rotations were measured in CHCl3 on an Anton Paar MCP 200 or on an Anton Paar MCP 100 Polarimeter using a sodium lamp (λ 589 nm, D-line). [α]D values are reported at a given temperature (°C) in degree·cm 2 ·g -1 with concentration in g/100mL.
HPLC analyses for the determination of enantiomeric excess were performed on a Merck-Hitachi system equipped with Chiralcel OD3, Chiralpak IA, Chiralpak IB, Chiralpak IB N-5, Chiralpak IE, and Chiralpak IJ analytical columns.
UV-vis and electronic circular dichroism (ECD) spectra were measured on a JASCO J-815 spectrometer equipped with a JASCO Peltier cell holder PTC-423 to maintain the temperature at 20.0 °C. A quartz photoelastic modulator set at l/4 retardation was used to modulate the handedness of the circular polarized light at 50 kHz. A quartz cell of 1 mm of optical path length was used.
Single crystal X-ray diffraction analysis were performed on a Rigaku Oxford Diffraction SuperNova diffractometer. Data collection reduction and multiscan ABSPACK correction were S3 performed with CrysAlisPro (Rigaku Oxford Diffraction). Using Olex2 [1] the structures were solved by intrinsic phasing methods with SHELXT [2] and SHELXL [3] was used for full matrix least square refinement.
The commercial solution of trimethylsilylmethylmagnesium chloride was titrated by reaction with benzaldehyde in diethyl ether (1.0 M) under an argon atmosphere at 23-25 °C, and its concentration determined by 1 H NMR by analysis of the crude reaction mixture.
All reactions with nonracemic substrates were optimized with racemic substrates, which furnished the racemic products that were necessary for the determination of suitable conditions for their resolution by analytical HPLC on chiral stationary phases.
To a solution of enantiopure (aR)-3,3'-bistrimethylsilyl-1,1'-binaphthyl-2,2'-diol (245 mg, 0.57 mmol, >99% ee) in anhydrous diethyl ether (10 mL) was added NaH (60% dispersion in oil, 114 mg, 2.90 mmol) at 0 °C. The resulting mixture was stirred at this temperature for 1 h and Tf2O (0.49 mL, 2.90 mmol) was added dropwise over 10 min. The reaction was then monitored by TLC until the starting material is no longer detectable (7 days) whereupon a saturated aqueous NH4Cl solution was added at 0 °C. The resulting mixture was extracted three times  The ee of (aR)-A was not confirmed by HPLC analysis because (aR)-A was found not suitable for the generation of the corresponding bis(aryne) atropisomer equivalent (see below). The structure and absolute configuration of (aR)-A were confirmed by X-ray diffraction analysis of a monocrystal (needles) obtained by slow evaporation of chloroform ( Figure S1, Table S1, CCDC 2173780). Figure S1. ORTEP representation of (aR)-A obtained by single-crystal X-ray diffraction analysis. The ellipsoids are drawn at the 50% probability level and H atoms are represented as fixedsize spheres of 0.15 Å radius. These measurements allowed the confirmation of the absolute configuration in (aR)-A.

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An attempt for the fluoride-induced generation of the bis(aryne) atropisomer synthetic equivalent from (aR)-A in the presence of 2,3,4,5-tetraphenylcyclopenta-2,4-dien-1-one produced only the known two-fold thia-Fries rearrangement product (aR)-C [7] in 56% yield after 2 hours with no detectable amount of the expected single-and/or two-fold cycloaddition/decarbonylation product (Scheme S1). A control reaction with benzyne under otherwise identical conditions afforded the expected tetraphenylnaphthalene derivative. Consequently, the Kobayashi-type precursor A was abandoned.
Scheme S1. Attempt for the fluoride-induced generation of the bis(aryne) atropisomer synthetic equivalent from (aR)-A.
In a round bottom flask, the aryne precursor (aS)-1 or (aR)-1 (100 mg, 0.12 mmol, 99% ee) was solubilized with 3 mL anhydrous toluene, the toluene was evaporated in vacuo, and the S11 flask was placed under an argon atmosphere (drying step). Then the flask was charged with Et2O and the arynophile under an argon atmosphere. The suspension was cooled down to 0 °C and trimethylsilylmethylmagnesium chloride (1.0 M in Et2O, 2.50 mL, 2.50 mmol) was added at this temperature over 4 hours. After stirring for a certain amount of time at 0 °C, the reaction mixture was hydrolyzed with water. The mixture was extracted three times with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product.
For products (aS)-2 and (aS)-3, the crude products obtained after the two-fold cycloaddition was directly diluted in anhydrous dichloromethane (2 mL), and NaI (90 mg, 0.60 mmol) and Me3SiCl (76 μL, 0.60 mmol) were subsequently added to the solution, resulting in an immediate dark brown coloration. The mixture was stirred at 23-25 °C until starting material is no longer detectable by TLC analysis (15 min). The reaction was hydrolyzed with a saturated NaHCO3 aqueous solution and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude product.
Following the general procedure 1 with (aS)-1 (100 mg, 0.12 mmol, >99% ee) and 2,5dimethylfuran (53 μL, 0.50 mmol) in 5 mL of Et2O for 16 hours afforded the crude intermediate oxa-bridged cycloadducts as a white solid (52 mg). This material was directly engaged in the deoxygenation reaction following the general procedure 2. Purification of the resulting crude product by flash chromatography eluted with pentane/Et2O = 50:1 afforded (aS)-2 (29 mg, 57% after the two steps) as a white solid. Solutions of (aS)-2 and (aR)-2 with a concentration of 0.15 mmol·L -1 were prepared in acetonitrile (HPLC grade). The CD spectrometer was purged with nitrogen during the recording of spectra. The UV absorption and ECD spectra were recorded using acetonitrile as a reference and are presented without smoothing and further data processing ( Figure S2). Atropisomer (aS)-2 exists in a single conformation which was optimized with Gaussian16 using DFT at the SMD(acetonitrile)/B3LYP-GD3BJ/6-311G(d,p) level of theory. 9,10,13,18b Based on the optimized geometry, the ECD and UV spectra were calculated using time dependent density functional theory with SMD(acetonitrile)/CAM-B3LYP/6-31++G(d,p). Calculations were performed for vertical 1A singlet excitation using 60 states. For a comparison between theoretical results and the experimental values, the calculated UV and ECD spectra have been modeled with a gaussian function, using a half-width of 0.37 eV. Due to the approximations of the theoretical model used, an offset almost constant was observed between measured and calculated frequencies. Using UV spectra, all frequencies were calibrated by a factor of 1.02. An excellent agreement was found between the experimental and simulated spectra of (aS)-2, confirming its absolute configuration. Figure S2. UV (left) and ECD (right) spectroscopic analyses of (aS)-2 and (aR)-2. In green color: experimental spectra of (aR)-2 recorded in CH3CN; in red color: experimental spectra of (aS)-2 recorded in CH3CN; in blue color: simulated spectra for (aS)-2 using SMD(acetonitrile)/CAM-B3LYP/6-31++G(d,p)//SMD(acetonitrile)/B3LYP-D3BJ/6-311Gd,p). S16 3,4-Dibromofuran was prepared by a known procedure.

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HPLC chromatogram of racemic 5 (Chiralpak IB N-5 column, heptane/dichloromethane = 95:5, 1 mL/min):   In a round bottom flask, the aryne precursor (aS)-1 (100 mg, 0.12 mmol, 99% ee) was solubilized with 3 mL anhydrous toluene, the toluene was evaporated in vacuo, and the flask was placed under an argon atmosphere (drying step). Then, the flask was charged with 5 mL of Et2O and 2,5-dimethylfuran (20 μL, 0.19 mmol) under an argon atmosphere. The suspension was cooled down to 0 °C and trimethylsilylmethylmagnesium chloride (1.0 M in Et2O, 2.50 mL, 2.50 mmol) was added at this temperature over 4 hours. The reaction was monitored by TLC and after stirring for 2 additional hours at 0 °C, anthracene (110 mg, 0.50 mmol) and trimethylsilylmethylmagnesium chloride (1.0 M in Et2O, 2.50 mL, 2.50 mmol) were subsequently added at this temperature. After stirring 16 h at 0 °C, the mixture was hydrolyzed with water, extracted three times with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the intermediate cycloadduct