One-Pot Synthesis of Difluorobicyclo[1.1.1]pentanes from α-Allyldiazoacetates

Rapid access to 2,2-difluorobicylco[1.1.1]pentanes is enabled from an α-allyldiazoacetate precursor in a one-pot process through cyclopropanation to afford a 3-aryl bicyclo[1.1.0]butane, followed by reaction with difluorocarbene in the same reaction flask. The modular synthesis of these diazo compounds affords novel 2,2-difluorobicyclo[1.1.1]pentanes that were inaccessible through previously reported methods. The reactions of chiral 2-arylbicyclo[1.1.0]butanes in the same manner generate altogether different products with high asymmetric induction, methylene-difluorocyclobutanes. Larger ring systems including bicyclo[3.1.0]hexanes are also rapidly furnished due to the modular nature of the diazo starting material.


General Considerations
All experiments were carried out in oven-dried glassware under argon atmosphere unless otherwise stated. Flash column chromatography was performed on silica gel. Unless otherwise noted, all other reagents were obtained from commercial sources (Sigma Aldrich, Fisher, TCI Chemicals, AK Scientific, Combi Blocks, Oakwood Chemicals, Ambeed) and used as received without purification. 1 H, 13C , and 19 F NMR spectra were recorded at either 400 MHz ( 13C at 100 MHz) on Bruker 400 spectrometer or 600 MHz ( 13C at 151 MHz) on INOVA 600 or Bruker 600 spectrometer. NMR spectra were run in solutions of deuterated chloroform (CDCl3) with residual chloroform taken as an internal standard (7.26 ppm for 1 H, and 77.16 ppm for 13C ), and were reported in parts per million (ppm). The abbreviations for multiplicity are as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet, dd = doublet of doublet, etc. Coupling constants (J values) are obtained from the spectra. Thin layer chromatography was performed on aluminum-back silica gel plates with UV light and cerium aluminum molybdate (CAM) or permanganate (KMnO4) stain to visualize. Mass spectra were taken on a Thermo Finnigan LTQ-FTMS spectrometer with APCI, ESI or NSI. IR spectra were collected on a Nicolet iS10 FT-IR spectrometer from Thermo Scientific and reported in unit of cm -1 . Enantiomeric excess (% ee) data were obtained on a Varian Prostar chiral HPLC instrument, an Agilent 1100 HPLC, or a Waters SFC, eluting the purified products using a mixed solution of HPLC-grade 2-propanol (i-PrOH) and n-hexane for HPLC, and a mixed solution of supercritical CO2 and acetonitrile+0.2% formic acid (MeCN+0.2%FA).

B-3: Synthesis of Synthesis of diazo compounds 19a-c:
First, the acetoacetate precursors were synthesized. Under an argon atmosphere, a solution of methyl 3-oxobutanoate (1.5 equiv) in anhydrous dimethoxyethane (DME) was added dropwise to a stirred suspension of NaH (60% suspension on mineral oil, 1.5 equiv) in anhydrous DME at 0 °C in 1 h. Then, n-Bu4NI (0.1 equiv) was added in one portion, followed by dropwise addition of trisubstituted allyl-bromide (1.0 equiv) in anhydrous DME at 0 °C over 1 h via addition funnel to generate a 1.5 M solution (relative to bromide starting material). The resulting mixture was then heated to 85 °C in an aluminum block and stirred overnight. After reaction completion, the mixture was cooled to 0 °C, diluted slowly with 1 N HCl, and extracted with ethyl acetate (EtOAc). The combined organic extracts were washed by brine, dried over anhydrous Na2SO4 and concentrated in vacuo. After a short flash chromatographic purification (0-10% EtOAc /hexanes), aggregation of product containing fractions and removal of solvent in vacuo, the resulting crude (Z)-trisubstituted α-allyl-acetoacetate was used directly in the next step. Nomenclature dictates the reassignment of the alkene geometry as "Z" after this synthetic step but the stereochemistry of the alkene is preserved throughout the synthesis.
Under an argon atmosphere, in a flame-dried RBF, crude Z-alkene (1.0 equiv) and p-acetamidobenzenesulfonyl azide (p-ABSA) (2.0 equiv) was dissolved in MeCN, to generate a 0.2 M solution of precursor, and the reaction mixture was cooled to 0 °C. DBU (4.0 equiv) was added dropwise at 0 °C. The reaction mixture was then warmed to room temperature and stirred overnight to afford a dark red solution. The crude reaction mixture was then extracted with EtOAc, washed by brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Sample was chromatographed (0-3% or 10% diethyl ether/hexanes for alkyl or aryl products respectively) and product containing fractions were aggregated. Solvent was removed in vacuo to afford the diazo as a bright yellow-orange oil. The products are indefinitely stable if refrigerated except for methyl (Z)-2-diazo-4-phenyloct-4-enoate which decomposed after 4 months at 0 o C.

S4
To a 16 mL flame-dried vial, kept under a dry atmosphere of argon, was added dry DCM (1.0 mL) and Rh2(Oct)4 (16 uL, c = 1.00 mg/ mL in DCM, 0.0001 equiv). Diazo compound (0.2 mmol, 1.0 equiv), dissolved in dry DCM (1 mL), was then added to the former solution drop-wise over 30 mins at room temperature via syringe pump. The 0.1 M reaction mixture was allowed to stir for another 15 min after the addition; when the diazo compound was fully consumed by IR analysis (disappearance of diazo (C=N2) stretch at ~2100 cm -1 ), the reaction mixture was concentrated in vacuo and analyzed by 1 H NMR in CDCl3 over K2CO3 to confirm the presence of bicyclo[1.1.0]butane product. Once bicyclo[1.1.0]butane presence was confirmed the solution was evaporated to dryness in vacuo. The mixture was then dissolved in THF (2 mL, 0.1 M). TMSCF3 (3 equiv) and NaI (0.5 equiv) were added to the solution. The resulting mixture was stirred at 65 °C overnight in an aluminum heating block. After completion, the reaction mixture was concentrated under reduced pressure, then the residue was dissolved in EtOAc, washed with DI water and brine, and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude product was purified by column chromatography (gradient, 0-10% Et2O /hexanes) and product containing fractions were aggregated. The solvent was removed in vacuo to afford the desired product in up to 65% yield.

General Method D:
One-pot synthesis of chiral methylene difluorocyclobutenes 26 and 27: To a 16 mL flame-dried vial, kept under a dry atmosphere of argon, was added dry EtOAc (1.0 mL) and Rh2(S-p-BrTPCP)4 (16 μL, c = 1.00 mg/ mL in EtOAc, 0.0001 equiv). Methyl (E)-2-diazo-5-phenylpent-4-enoate (0.2 mmol, 1.0 equiv), dissolved in dry EtOAc (1 mL), was then added to the former solution drop-wise over 30 mins at room temperature via syringe pump. The 0.1 M reaction mixture was allowed to stir for another 15 min after the addition; when the diazo compound was fully consumed by IR analysis (disappearance of diazo (C=N2) stretch at ~2100 cm -1 ), the reaction mixture was concentrated in vacuo and analyzed by 1 H NMR in CDCl3 over K2CO3 to confirm the presence of bicyclo[1.1.0]butane product. Once bicyclo[1.1.0]butane presence was confirmed as the spectra matched those reported in the literature, the solution was evaporated to dryness in vacuo. The mixture was then dissolved in THF (2 mL, 0.1 M). TMSCF3 (3 equiv) and NaI (0.5 equiv) were added to the solution. The resulting mixture was stirred at 65 °C overnight in an aluminum heating block. After completion, the reaction mixture was concentrated under reduced pressure, then the residue was dissolved in EtOAc, washed with DI water and brine, and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude product was purified by column chromatography (gradient, 0-2% Et2O /hexanes) and product containing fractions were aggregated. The solvent was removed in vacuo to afford the desired products in up to 74% yield as a 2:1 mixture of methylene difluorocyclobutenes. The products appear as a single peak, to separate them one must collect low volume fractions (3-5 mL) and NMR each vial individually. Additionally, the products are unstable upon isolation and lose difluoromethane to generate a diene.