Cyclopropanation of Chalcones

The Corey-Chaykovsky reaction will be used to cyclopropanate your chalcone from Experiment 61. The reaction involves the reaction of trimethylsulfoxonium iodide and potassium fcrf-butoxide in anhydrous dimethylsulfoxide (DMSO). The reaction is stirred at room temperature for 1 hr. For example, frans-chalcone (1,3-diphenyl-2-propen-l-one) produces an 88% yield of the cyclopropanated product. You will analyze your product by NMR and infrared spectroscopy. 

Dispose of all aqueous wastes in the container designated for aqueous waste. Place the organic waste in the nonhalogenated organic waste container. Methylene chloride should be placed in the halogenated waste container. 

Chalcones usually react completely in the cyclopropanation reaction, leaving little or no starting chalcone in the product. 

Dissolve the 0.50 mmole of the chalcone from Experiment 61 in 2.0 mL of anhydrous dimethylsulfoxide (DMSO) in a 25-mL roimd-bottom flask. Allow the solid to dissolve. Add a stir bar. Add to the solution a dry mixture of MegS(0)l and KO-tert-butoxide (0.20 g, 0.6 mmol) in one batch. Now add a drying tube filled with CaCl2 to the flask. Stir the solution for 1 hour at room temperature. 

Transfer the mixture to a separatory funnel, and add 25 mL of saturated aqueous sodium chloride solution, using some of the sodium chloride solution to aid in the transfer of the reaction mixture to the funnel. Extract the mixture with a 15-mL portion of diethyl ether. Remove the lower aqueous layer, and pour the ether layer from the top of the separatory funnel into a beaker. Return the aqueous layer to the funnel, and re-extract it with another 15-mL portion of diethyl ether. Combine the two ether layers in the same beaker. Pour the ether extracts back into the separatory funnel, and re-extract the ether layer with two 25-mL portions of water, followed by extraction with 25 mL of saturated sodium chloride, each time draining the lower aqueous layer and saving the ether layer. 

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Johnson first described the cyclopropanation of chalcone using lithiated /V-tosyl 5-alkyl-5-phenylsulfoximines in 1973.18 In one example, an optically active (ee 49%) cyclopropane [(15, 25)-(2-phenylcyclopropyl) phenyl ketone] was prepared from the reaction of chalcone and lithiated (R)-N-tosyl-5-methyl-5-phenylsulfoxi-mine (ee 84%) at room temperature for 12 h. More recently a solid-state version of this reaction was reported.57 Treatment of a mixture of powdered chalcone, (+)-N-tosyl-5-methyl-5-phenylsulfoximine 2b, and KOH in the solid state at 70 °C gave optically active phenylcyclopropyl phenyl ketone 75a in poor yield (19%) and... 

Scheme 7.84 Enantioselective cyclopropanation of chalcones via sulfonium and telluronium ylides.

Synthesis of Naproxen (Aleve ) by palladium catalysis Green Epoxidation of Chalcones Cyclopropanation of Chalcones... 

A carbon labelling study has elucidated the rearrangement mechanism for formation of chalcone (97) which accompanies formation of (91) by the expected vicinyl elimination of trimethylsilyl and benzotriazolyl groups from 2-benzotriazolyl-2-aryl-3-ketopropylsilanes, on reaction with fluoride ion in DMF. ° Thus, it has been possible to distinguish between the two alternative mechanisms depicted in Scheme 11 (via intermediates (93) or (95), respectively, by determining the fate of the labelled quaternary carbon of substrate (89). The results are consistent with the formation of a cyclopropane intermediate (95) which subsequently ring opens, with relief of strain, to form delocalized carbanion (96), from which the chalcone (97) is obtained (labelled... 

Tetralone synthesis. Murphy and Wattanasin- have devised a simple tetralone synthesis involving cyclization of aryl aroyl cyclopropanes. A chalcone (2) is cyclo-propanated by 1 to give a 1 1 mixture of 3 and 4, which can be separated. This step is not necessary since 4 is readily epimerized to 3 under the conditions for... 

In contrast to the above described reactivity of dimethylsulfonium trimethylsilylmethylide (2), triphenylarsonium trimethylsilylmethylide (5) is able to cyclopropanate the C-C double bond of chalcone [( )-l,3-diphenylpropenone] and some of its derivatives. The arsonium ylide is prepared in situ from (trimethylsilylmethyl)triphenylarsonium tetraphenylborate (4) by deprotonation with phenyllithium. The reactions with various substituted chalcones were carried out at room temperature and at — 70 "C. Although the yields achieved for cyclopropanes 6 are almost equal, the formation of the -isomer predominates at lower temperature whereas at room temperature the isomer ratio is nearly 1 1. 

The reaction of hydrazine with a,/S-unsaturated aldehydes and ketones (the anomalous Wolff-Kishner reaction, Houben-Weyl, Vol. 4/3, p71) sometimes provides a one-pot procedure in which the cyclopropane is formed directly, but often the intermediate 2,3-dihydro-l//-pyrazole is isolated and heated either alone or with a basic catalyst to effect elimination of nitrogen. Hence in the conversion of chalcone to 1,2-diphenylcyclopropane the intermediate 3,5-diphenyl-2,3-dihydro-l//-pyrazole (10) was isolated and heated with potassium hydroxide. 

Another multistep synthesis, shown below, involves linking the synthesis of a chalcone in Experiment 61 with the epoxidation of the chalcone (Experiment 62) and/or the cyclopropanation of the chalcone (Experiment 63). If you plan for creating a multistep synthesis as described here, it may be a good idea to make a larger quantity of chalcone by scaling up the amounts of substituted acetophenone and substituted benzaldehyde used to prepare the chalcone. 

The reaction of chalcones and trimethylsulphonium iodide and KOH in the solid state gave the corresponding cyclopropanes (Scheme 42). 

The same cyclopropane derivative was also obtained by the reaction of chalcone with (+)-S-methyl-S-phenyl-N-(p-tolyl)sulfoximide and tert. BuOK at room temperature in 94% yield (Scheme 43). 

Achiral tellurides were used in the catalytic epoxidation of aldehydes by Huang and coworkers in 1990. With diisobutyl telluride as a catalyst (20mol%), various aromatic, heteroaromatic, and non-primary aliphatic aldehydes can be epoxidized directly with aUyhc bromide to the corresponding vinyl epoxides in good yields with predominantly cis-selectivity [59], Later, they successfully extended this method to the cyclopropanation of a,(3-unsaturated ketones with aUyl bromides [60], The asymmetric version of the cyclopropanation was realized by Tang and coworkers in 2003 [61], using salt 43 directly as a catalyst (20mol%) in the reaction of chalcones with silylated aUyl bromide. The desired vinyl cyclopropanes were... 

The best results were obtained with 20 mol% camphor-derived sulfonium salt 230, with 1.5 equivalents of 3-phenylallyl bromide and one equivalent of chalcone at 0°C in a mixture of fert-butyl alcohol and acetonitrile (2.5 1). The cyclopropanation product was obtained in moderate diastereoselectivity (86/14), good enantiose-lectivity (82% ee) and in high yield (92%). The method could be extended to a variety of a,P-unsaturated carbonyl compounds (Table 7.16). The chiral sulfide 228 could also be employed directly without preformation of the sulfonium salt 230 with similar results. 

Phase-transfer catalytic conditions provide an extremely powerful alternative to the use of alkali metal hydrides for the synthesis of cyclopropanes via the reaction of dimethyloxosulphonium methylides with electron-deficient alkenes [e.g. 54-56] reaction rates are increased ca. 20-fold, while retaining high yields (86-95%). Dimethylphenacylsulphonium bromide reacts in an analogous manner with vinyl-sulphones [57] and with chalcones [58] and trimethylsulphonium iodide reacts with Schiff bases and hydrazones producing aziridines [59]. 

Recently, Tang, Wu and co-workers have reported the synthesis of vinylcyclopro-panes using an alternative catalytic cycle for sulfur ylide-catalyzed cyclopropanation (see Scheme 10.22) [98]. Sulfonium salt 41a or 41b was deprotonated by CS2CO3 to form an ylide which then reacted with chalcones 37 to form cyclopropanes and a sulfide. The sulfonium salt was regenerated in situ through reaction... 

Trimethylsilylmethylenetriphenylarsorane, in contrast to trimethylsilylmethylenesul-phurane, could also react with substituted chalcones to give silylcyclopropanes (266) (equation 80). Reaction of phosphoranes (267) with crotonates gives rise to electrophilic cyclopropanes (268) (equation 81) . However, the reaction of methyl... 

Aroylcyclopropanecarboxylates 13 were obtained by reaction of ethyl cyanoacetate with a.,p-unsaturated carbonyl compounds in the presence of sodium powder. Even relatively crowded chalcones were converted into the corresponding 2-aroylcyclopropanecarboxylates in high yields. 2-Aroylcyclopropanecarboxylates have also been synthesized using other cyclopropan-ating agents. ... 

The catalysts leading to the higher trans and cis preferences, namely Cu(II)-bentonite and Cu(II)-K10, were tested in the reactions of ethyl diazoacetate (1) with different alkenes (Scheme 2). The results obtained (Table 2) show that the yield and the selectivities with regard to both reagents increase with the electron-donor ability of the substituents of the double bond, which indicates the electrophilic character of the reaction. Therefore the cyclopropanes coming from chalcone (10) could not be obtained. 

Cobalt(III)-SALEN complexes (see Fig. 20) were found to be efficient catalysts for asymmetric cyclopropanation (184). Co(acac)2 in the presence of chiral amino alcohols (derived from camphor) has been employed as a catalyst for the enan-tioselective addition of diethylzinc to chalcone (185). Axially chiral SALEN-type ligands possessing biphenyl-core as an element of chirality are efficient ligands for the enantioselective addition of diethylzinc to aldehydes. The formation of bimetallic species forming a chiral pocket was shown (186). 

A four-step synthesis may be considered by linking together the Friedel-Crafts reaction with the synthesis of a chalcone (Experiment 61) and then preparing an epoxide (Experiment 62) from the chalcone and/or a cyclopropanated chalcone (Experiment 63). It is likely that the Friedel-Crafts reaction should produce enough acylated product for the reactions that follow. If you choose to link together the chalcone synthesis followed by epoxidation and cyclopropanation, it is suggested that you choose to prepare the acetyl derivatives of toluene, p-xylene, mesitylene, or anisole and use one of the recommended aldehydes shown in the following table to make the chalcone in Experiment 61. 

Check the purity of fhe producf by TLC. Dissolve a small amount of the product in methylene chloride, and spot it on the plate. Also spot a dilute solution of the starting chalcone on the plate. Develop the plate in methylene chloride, and use the UV lamp to visualize the spots to see if fhere are any by-producfs or starting chalcone in your cyclopropanated product. 

Summarize the changes you expect to observe in the IR and NMR spectra of your cyclopropane product relative to the chalcone starting material. 

B. Poly (ary I ether)s containing a 1,2-diphenylcyclopropane moiety. We have recently reported a very simple synthesis of the cyclopropane containing bisphenol 13 in two steps from the chalcone 11. ... 

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