Synthesis of spiro-cyclics via ring-closing metathesis

Various spiro-cyclic systems were synthesized by utilizing ring-closing metathesis as a key step. The required dialkylated starting materials were prepared from various 1,3-diketones or substrates containing an active methylene group

Various approaches to prepare spiro-cyclics have encountered problems associated with functional group incompatibility at one or more stages and restricted to a single substitution pattern.In only a few instances, was the newly generated ring system left with a useful functionality for further transformations.Therefore, there is a need to develop new methods for the preparation of the spiro-linkage under milder reaction conditions with additional functionality for further synthetic manipulation.Herein, we report the full details of our methodology for the preparation of spiro-cyclic compounds using ring-closing metathesis (RCM) as a key step.8c

Results and Discussion
In order to demonstrate the spiro-annulation shown in equation 1 our immediate task was to prepare diallylated compounds.In this regard, we have chosen commercially available 1,3diketones such as dimedone, 1,3-cyclohexanedione, 1,3-cyclopentanedione 5 and 1,3indanedione 6 and compounds containing an active methylene group (e.g.fluorene 7 and anthrone 8) as our substrates.
Although several methods are available in the literature for diallylation of active methylene compounds, 1,3-diketones pose a special problem because of unwanted O-alkylation.In this regard, Lapintskaya and Pivnitskii reported 9 a novel method for C-alkylation of cyclic-diketones by allyl acetate in a weakly acidic medium with Pd(PPh 3 ) 4 as a catalyst. 10This method allows the preparation of the mono-and diallylated products.Based on this precedence, dimedone was reacted with allyl acetate in the presence of Pd catalyst, [Pd(PPh 3 ) 4 ] in THF at RT for 1 h (Scheme 1) to give the diallyl dione 9. Similarly, the preparation of the other diallyl derivative 10 was achieved by following the above general procedure, whereas compound 11 was prepared by using DBU as a base during the alkylation step. 11However, compound 12 was initially prepared under similar conditions (DBU/[Pd(PPh 3 ) 4 ]), only as a minor product.Later on, the reaction conditions were standardized to deliver the required diallyl compound 12 as the sole product.We have also found that the phase-transfer conditions [K 2 CO 3 , tetrabutylammonium hydrogen sulfate (TBAHS) and CH 3 CN], developed in our laboratory in connection with an amino acid project 12 and also other basic conditions gave good yields of dialkylated products 9, 10 and 12. Reaction of potassium metal with fluorene 7 in dioxane at 110 o C for 5 h according to the reported procedure gave 9,9-diallyfluorene 13. 13 In some cases 1,3-diketone derivatives were allylated using KF/celite conditions. 14The diallyl anthrone 14, was prepared by treating the anthrone 8 with allyl bromide. 15aving obtained various diallylated products in fair yield, the next task was to demonstrate the key RCM reaction.Initially the diallyl dione 9 was subjected to RCM reaction [16][17][18] by reacting with catalytic quantities of Grubbs' catalyst 15 in CH 2 Cl 2 at RT for 12 h.At the conclusion of the reaction (TLC monitoring), the solvent was evaporated at reduced pressure and the crude product was purified by chromatography using EtOAc-Hexane (3:97) as eluent to afford the required spiro-derivative 16 (95%, mp 95-96 o C, Scheme 2).Along similar lines, various spiro-systems were prepared (Table I) and fully characterized by their spectral data.Some of the RCM products deserve special mention.For example, substrates 18 and 19 constitute the CD and BCD rings of fredericamycin 1 structure.Similarly, many of the RCM products reported in Table I are potential precursors for various unknown fenestrane frames.

Conclusions
We have succeeded in developing a general and versatile method for the synthesis of several spiro-cyclic systems.The RCM method developed here offers very mild reaction conditions for the direct formation of spiro-compounds with an additional double bond for further synthetic manipulation.The flexibility of this method has been demonstrated via the synthesis of various spiro-cyclic systems and the methodology described here may find interesting applications in the synthesis of natural and non-natural products.Experimental Section General Procedures.Melting points were recorded on Labhosp or Veego melting point apparatus and are uncorrected.Boiling points refer to the bath temperatures.Room temperature (RT) refers to ~35 0 C. Infrared (IR) spectra were recorded on Nicolet Impact-400 FT IR spectrometer.Solid samples were recorded in KBr/CHCl 3 /CCl 4 and liquid samples as their thin film between NaCl plates and the absorptions are reported in cm -1 .Ultraviolet spectra were recorded on Shimadzu UV-2100 or UV-260 instruments.Proton Nuclear Magnetic Resonance ( 1 H NMR) spectra were generally recorded on EM-360 (60 MHz) or Varian VXR 300 (300 MHz) spectrometers.Carbon Nuclear Magnetic Resonance ( 13 C NMR) spectra were generally made in chloroform-d solvent and chemical shifts were reported in delta scale using tetramethylsilane (TMS) as the internal standard.Mass spectral measurements were carried out on GCD 1800 Hewlett-packerd GS-MS spectrometer.Elemental analysis was performed on Carlo-Ebra MOD 1106 CHN analyzer.Analytical thin-layer chromatography (TLC) were performed on (10 × 5 cm) glass plates coated with Acme's silica gel G or GF 254 (containing 13% calcium sulfate as a binder).The column is usually eluted with ethyl acetate-petroleum ether (60-80 o C) mixture.Grubbs' catalyst was purchased from Strem Chemical Co.The known compounds 9, 10 and 12 prepared in the present study by a different route are verified by 1 H NMR spectral data.
By following PTC method: 12 To a mixture of indane-1,3-dione 6 (37 mg, 0.25 mmol) and allylbromide (0.02 mL, 0.25 mmol) in CH 3 CN (8 mL) was added K 2 CO 3 (35 mg, 0.25 mmol) and TBAHS (9 mg, 0.025 mmol) and the mixture was stirred for a period of 8 h.Then, the reaction mixture was filtered off and the filtrate was concentrated to give the crude product which was purified on a silica gel column by eluting with ethyl acetate and petroleum ether mixture (4:96) to afford the diallyl product 12 (30 mg, 53%).