Ring closing metathesis and metal-catalyzed cyclopropanation for the preparation of sultone derivatives

Ring closing metathesis (RCM) using Grubbs catalyst 2 generation as a catalyst was applied to prepare series of novel unsaturated sultones with high yields. Many attempts, were applied for the cyclopropanation of the allylic sultones by Simmon-smith cyclopropanation using diethyl zinc/diiodomethane or Zn-Cu/diiodomethane but in each case the corresponding cyclic adduct was not formed. A novel palladium or preferably rhodiumcatalyzed cyclopropanation of unsaturated sultones with ethyl diazoacetate was achieved by the transition metal-catalyzed transfer of a CH-CO2Et unit. The reaction was applied by a portion-wise addition of ethyl diazoacetate over 6h to a mixture of the sultones and palladium(II) acetate or rhodium(II) acetate dimer under low temperature (0-20 o C). The desired products of the cyclopropanation were achieved in each case, as a single diastereomer with 3337% yield in the allylic sultones and 10% for vinylic sultone.


Results and Discussion
In this study, several allylic and vinylic sultones were prepared from the appropriate sulfonate and Subsequent RCM.The unsaturated sulfonates (3) were prepared from the reaction of the primary or secondary alkenols (2a,b) with allyl sulfonyl chloride (1), in the presence of TEA, under low temperature.We apply our modified procedure to obtain high yields of the sulfonates (3) via completing the addition process of the reactant under -20 o C and left the reaction under this temperature for 4 h (Scheme 1).
RCM was achieved by portion wise addition of Grubbs catalyst 2 nd generation under reflux temperature on a solution of the unsaturated sulfonate 3a or 3b to afford the corresponding sultone (4a,b).the structures of the sultones (4a,b) were confirmed by the elemental analysis and spectral data.The 1 H-NMR spectrum of the 4b revealed doublet signal at 1.35 ppm corresponding to CH 3 , multiplets near 5.63, 6.01 ppm for 2 allylic CH .Since there was only a single publication on the intermolecular cyclopropanation of vinylic 27 or allylic sultones prior to our work we decided to investigate this transformation.
Many attempts, in this study, were applied for the cyclopropanation of the sultones 4a,b by Simmons-Smith cyclopropanation using diethyl zinc/diiodomethane or Zn-Cu/diiodomethane, but in each case the cyclopropanation for the corresponding cyclic adduct was not obtained (Scheme 1).The successful attempts and the first investigation for the cyclopropanation of the sultones 4a,b with ethyl diazoacetate to give the desired products as single diastereomers were achieved by palladium(II) acetate or rhodium(II) acetate dimer as a catalyst.The cyclopropanation reaction was achieved via transition metalcatalyzed transfer of a CH-CO 2 Et unit under low temperature 0-20 o C. with continuous and slow addition of ethyl diazoacetate over 6 h.

Scheme 1
To complete the overall picture for the preparation of novel sultones we have designed the synthetic pathway to prepare new vinyl sultones as presented in scheme 2. Firstly, the secondary allylic alcohols were prepared from the corresponding ketone using LiAlH 4 .Ethenesulfonyl chloride (10) was prepared in-situ from the treatment of chloro ethyl sulfonyl chloride (9) with TEA under low temperature.The unsaturated sulfonate derivatives (11) were readily prepared by esterification of the secondary alcohols (8) with the in-situ generated ethenesulfonyl chloride (10) in the presence of TEA under low temperature (-40 o C).The structures of the formed sulfonates were confirmed by elemental analysis and spectral data.
In this study, the second new series of sultones is the vinyl sultones (12) prepared by treatment of the freshly prepared vinyl sulfonate (11) with Grubbs(II) catalyst that added portion wise under reflux temperature (Scheme 2).The structures of the new vinyl sultones were confirmed by elemental analysis and spectral data.(See the experimental part).
Several attempts were applied for the cyclopropanation of the vinyl sultones 12 using sulfur yields; trimethylsulfonium bromide (CH 3 ) 3 S + Br − , in the presence of potassium tert-butoxide in DMF but in each case lead to decomposition of the sultones due to the base; potassium tert-butoxide.Cyclopropanation of the vinyl sultones 12b, was achieved with very low yield (10%) by treatment with ethyl diazoacetate in the presence of dirhodium(II) tetra acetate as a catalyst under low temperature 0-20 o C. the cyclopropanation was not achieved by palladium(II) acetate as catalyst (Scheme 2).The constitution of the bicyclic sultone 14 was confirmed by the elemental analysis and spectral data, while the relative configuration was tentatively assigned in analogy to sultones 6.The 1 H-NMR spectrum of the sultone 14 revealed presence of 3 characteristic bands multiplets near 0.97, 1.15 and 1.70 ppm corresponding to the cyclopropane protons; 6-H, 4-H, and 5-H, respectivly.Two signals that are charactarestic for the ester group were appeared as triplet and quartet at near 1.10 and 4.22 ppm, respectivly.the 2-allylphenol (15) with ethenesulfonyl chloride (10), in the presence of TEA under low temperature (0-40).The unsaturated sulfonate derivative ( 16) was formed with 78% yield and its structure was confirmed by elemental analysis and spectral data.The vinyl sultone (17) was prepared with 90% yield by treatment the sulfonate 16 with Grubbs catalyst 2 nd generation under reflux temperature in DCM (Scheme 3).
The 1 H-NMR spectrum of the sultone ( 17) revealed bands at 3.72 (m), 6.35 (m) and 6.48 (m) ppm corresponding to CH 2 and 2CH, respectivly.The aromatic protons apperd at 7.21-7.45ppm.The structure of the sultone (17) was fully confirmed by the X-ray single crystal analysis (Figure 1).We have tried to apply the cyclopropanation reaction on the later sultone by different treatments with ethyl diazoacetate in the presence of Pd(OAc) 2 or Rh 2 (OAc) 4 but in each case there was no reaction.

Conclusions
In this study, a novel palladium-or preferably rhodium-catalyzed cyclopropanation of unsaturated sultones with ethyl diazoacetate to give the desired products as a single diastereomer have been achieved.These densely functionalized heterocycles are surely highly interesting intermediates for the preparation of pharmaceutically active compounds.The unsaturated sultones required for these investigations were readily available by esterification of unsaturated alcohols with sulfonyl chlorides and subsequent ruthenium-catalyzed ring-closing metathesis.With a range of novel sultones synthesized in this fashion, we first investigated different conditions for cyclopropanation using the Simmons-Smith methodology and also sulfur ylide chemistry to transfer an un-substituted methylene unit to the alkene moiety of the substrates.Whereas these reactions did not work with the unsaturated sultones at hand, the transition metal-catalyzed transfer of a CH-CO 2 Et unit finally succeeded as detailed above.Probably, the cyclopropanation of the vinylic sultones was more difficult than the allylic sultones due to the high electron deficiency of the alkenes of the vinylic sultone.But in case of the allylic sultones where the separation of the sulfonyl group and the olefin by CH 2 group might allow a [2+1] cycloaddition to give the desired cyclopropanes © ARKAT USA, Inc

Experimental Section
General.Infrared spectra were recorded on a THERMONICOLET Avatar 360 instrument using ATR.NMR spectra were recorded on a Bruker AC 300 P (300 MHz 1 H, 75 MHz 13 C), on a Bruker DRX 500 P (500 MHz 1 H, 125 MHz 13 C) or on a Bruker AC 600-P (600 MHz 1 H, 151 MHz 13 C) spectrometer.Chemical shifts () are quoted in parts per million (ppm) downfield of tetramethylsilane, using residual proton-containing solvent as internal standard (CDCl 3 at 7.26 ppm).Abbreviations used in the description of resonances are: s (singlet), d (doublet), t (triplet), q (quartet), br (broad).Coupling constants (J) are quoted to the nearest 0.1 Hz.Mass spectra were recorded with an Agilent 5973N detector coupled with an Agilent 6890N GC (GC-MS, 70 eV) or else with a Bruker Esquire-LC (direct injection as a methanolic NH 4 OAc solution, ESI).HRMS spectra were recorded on a Bruker Daltonic "Impact II" (ESI-TOF).Elemental analysis was performed on a Hekatech EA 3000.

Preparation of prop-2-ene-1-sulfonyl chloride (1).
Prop-2-ene-1-sulfonyl chloride (1) was prepared by our modification on the reported method 28 as in the following: To a stirred solution of allyl bromide (12.10 g, 0.1mol) in 100 mL distilled water was added Na 2 SO 3 (15 g, 0.12mol).The reaction mixture was refluxed for 8h then left to cool to room temperature.The reaction mixture was washed with Et 2 O several times and the aqueous layer was evaporated under reduced pressure.The crude product was washed with methanol, filtered off and left to dry to afford (10.2g, 0.07 mol, 71% yield) of sodium allysulfonate.The latter crude product was stirred at zero temperature with 30 mL of POCl 3 for 1/2 h then refluxed for 5 h and left to cool to room temperature.100 mL of THF was then added to the mixture then filtered off and washed several times with dry THF.The filtrate was evaporated carefully on rotavapor and the residue was distilled under vacuum (5 mbar).Allylsulfonyl chloride was separated with boiling point range 37-43 o C as coreless oil (71%).

General procedure for the preparation of but-3-enyl prop-2-ene-1-sulfonate derivatives (3a,b).
To a stirred solution of the unsaturated alcohol (2a,b) (1.0 equiv.)and dry TEA (1.5 equiv.) in CH 2 Cl 2 at low temperature (-20 o C) was added ally sulfonyl chloride (1.2 equiv.) in CH 2 Cl 2 drop by drop.The reaction mixture was left to stir under this temperature for 4 h then left to stir for 0.5 h at room temperature.Pentane was then added and the mixture was filtered through Celite.The filtrate was concentrated under reduced pressure and the crud residue was purified by flash chromatography.