Preparation and Synthetic Applications of Phototropone

An optimized multigram-scale route to phototropone (bicyclo[3.2.0]hepta-2,6-dien-7-one) is reported via the 4-π-photocyclization of tropone complexed to Lewis acid. Phototropone is a highly versatile molecular building block, and its conversion into 18 novel derivatives using standard transformations is demonstrated, allowing access to a variety of rigid bicyclic scaffolds.


S3
Analytical TLC was carried out on pre-coated aluminium-backed TLC plates (silica gel 60 F254) and visualised by UV light (254 nm) or stained with potassium permanganate as developing agent. Flash chromatography on silica gel was performed with silica gel from VWR (40-63 microns). 1 H and 13 C NMR spectroscopic data were collected on a Bruker Ultrashield 400 Plus instrument and chemical shifts are reported in parts per million (δ) calibrated to residual CHCl3 (δH = 7.26 ppm) and CDCl3 (δC 77.0 ppm, central line). The following abbreviations are used to describe the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and br = broad. Coupling constants (J) are given in Hertz. Assignment of the signals in 1 H and 13 C NMR spectra was achieved using 2D-NMR techniques (COSY, HSQC and HMBC). When using 1 H NMR to monitor the reaction progress, solvent suppression was used to supress the signal arising from the non-deuterated solvent. Infrared (IR) spectra were recorded on an Agilent Technologies Cary 630 FTIR spectrometer. High resolution mass spectrometry data were recorded using electron spray ionization (ESI) or atmospheric pressure chemical ionization (APCI) on a Shimadzu LCMS-IT-TOF mass spectrometer. Melting points were performed on a Sanyo Gallenkamp capillary melting point apparatus and are uncorrected.

Bicyclo[3.2.0]hepta-3,6-dien-2-one 1
A solution of tropone (1.9 mL, 17.6 mmol) and BF3•OEt2 (2.4 mL, 19.5 mmol) in anhydrous CH2Cl2 (390 mL) was distributed between six 70-mL Duran phototubes, and each tube was bubbled with Ar gas for 10 minutes before being irradiated at 300 nm for 10 hours. This process was repeated with a further six phototubes, then the tube contents were combined and the solvent was removed under reduced pressure (500 mbar) to yield the crude product. Purification by flash chromatography on silica gel with CH2Cl2 → 95:5 CH2Cl2-Et2O as the eluent gave 1 (3.1 g, 2.07 mmol, 75%) as a yellow oil. NB The product is volatile and should not be subjected to high vacuum.

Data for 9:
Rf (pentane-CH2Cl2, 1:1) = 0.24 NB Tertiary alcohol 10 was found to be somewhat unstable towards purification on silica/alumina, resulting in some degradation during the purification process. Further derivatization of the crude product is advisable prior to purification.

4-Ethenylbicyclo[3.2.0]hepta-3,6-dien-2-one 11
A solution of vinylmagnesium bromide (1.7 mL of a 0.89 M solution in THF) was added dropwise to a solution of 1 (106 mg, 1.00 mmol) in THF (5 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 12 hours. A 0.5 M aqueous solution of HCl (10 mL) was added, and the reaction mixture was extracted with diethyl ether (3 x 10 mL). The combined organic layers were dried (MgSO4) and evaporated under reduced pressure to yield the crude tertiary alcohol product. PDC (752 mg, 2.00 mmol) was added in one portion to a solution of the crude tertiary alcohol product in CH2Cl2 (5 mL), and the resulting suspension was stirred at room temperature for 12 hours, then diluted with diethyl ether (5 mL), filtered through Celite and evaporated under reduced pressure to give the crude product.
Purification by flash column chromatography on silica gel with CH2Cl2 as the eluent gave 11 (86 mg, 0.65 mmol, 65%) as a colourless oil.

rac-(1R,2R,5R)-Bicyclo[3.2.0]hepta-3,6-dien-2-ol epi-9
Triethylamine (0.14 mL, 1.00 mmol) was added to a stirred solution of hydrazine monohydrate (0.13 mL, 1.00 mmol) in MeCN (2.5 mL) at room temperature, and the resulting solution was stirred at room temperature for 20 minutes. A solution of 17 (94 mg, 0.76 mmol) in acetonitrile (2.5 mL) was added in one portion at room temperature and the resulting solution stirred for a further 20 minutes. Glacial acetic acid (0.065 mL, 1.14 mmol) was then added at room temperature and the solution was stirred S13 for a further five minutes. The reaction mixture was diluted with water (5 mL) and was extracted with Et2O (3 x 10 mL). The combined organic layers were dried (MgSO4) and evaporated under reduced pressure to yield the crude product. Purification by flash column chromatography on silica gel with 1:1 pentane-CH2Cl2 as the eluent gave epi-9 (48 mg, 0.44 mmol, 59%) as a colourless oil.
Rf (pentane-CH2Cl2, 1:1) = 0. m-CPBA (516 mg, 2.31 mmol) was added dropwise to a stirred solution of 1 (106 mg, 1.00 mmol) in dry dichloromethane (2 mL) at 0 °C under argon, and the resulting suspension was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 24 hours before being diluted with saturated aqueous NaHCO3 (2 mL) and extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were dried (MgSO4) and evaporated under reduced pressure to give the crude product.