Cyclopropanations ethyl acetate

A mixture of norcodeine hydrochloride (11.48 g, 27.8 mmol), (chloromethyl)cyclopropane (5.14 g, 55.6 mmol), sodium carbonate (14.73 g, 139.0 mmol), and potassium iodide (4.61 g, 27.8 mmol) in ethanol (250 ml) was heated at reflux for 20 hr, cooled, and evaporated in vacuo to dryness. The residue was basified with NH4OH, and extracted with methylene chloride. The extract was washed with water and evaporated in vacuo to dryness. The residue (11.7 g) was chromatographed on silica gel with a eluting solvent system of methanol/ethyl acetate (10/90) to give 17-cyclopropylmethylnorcodeine (10.68 g, 91% yield). 

To a 10-mL round-bottomed flask fitted with a nitrogen balloon was added sulfide catalyst (0.2 equiv), anhydrous dioxane (4.0 mL), rhodium(II) acetate dimer (2 mg, 0.01 equiv), substrate (0.5 mmol), benzyl triethylammonium chloride (23 mg, 0.2 equiv), and tosylhydrazone sodium salt (1.5 equiv). The reaction mixture was stirred vigorously at 40 °C for 48 h. Work-up consisted of the sequential addition to the reaction mixture of water (5 mL) and ethyl acetate (5 mL). The aqueous layer was washed with ethyl acetate (2.5 mL) and the combined organic phases dried (MgSC ), filtered, and concentrated in vacuo. The crude products were analyzed by aH NMR to determine the diastereomeric ratio, and then purified by FC to afford the corresponding cyclopropane. 

Another more recent example of a cheletropic reaction, studied in various solvents, is the addition of aryl-halocarbenes (generated photolytically from diazirines) to tetramethylethene to give the corresponding cyclopropane derivatives [820], The addition of chlorophenylcarbene is only about three times faster in ethyl acetate than in pentane, as befits an isopolar activated complex. 

C. (+)-(lS,2S>-Cyolopvopane-ljZ-diBarboxylio aoid. (-)-Dimenthyl (lS,2S)-cyclopropane-l,2-dicarboxylate (4.06 g, 10 mmol, +17.8°) Is dissolved in 20 ml of a 10% potassium hydroxide solution in 9 1 methanol/water In a 50-mL, one-necked, round-bottomed flask equipped with a magnetic stirring bar. The solution is heated at 60°C with an oil bath. Progress of the reaction is monitored by TLC on silica gel, using 1 1 hexane/ethyl acetate as eluant (Note 15). After about 4 hr the resulting two-phase mixture Is diluted with 20 mL of water and extracted with three 40-mL portions of ether (Note... 

The a proton of a substituted cyclopropane is also rendered acidic if the substituent is attached to the ring by C-P bonds. A few reports have appeared on a-substitution in such compounds.(Cyclopropyl)triphenylphosphonium bromide was converted to a (1-ethoxy-carbonylcyclopropyl)triphenylphosphonium salt 18 in 80% yield by sequential treatment with lithium diisopropylamide and ethyl chloroformate. Furthermore, some diethyl cyclopropyl-phosphonates were converted, in some cases in excellent yield, to diethyl (1-hydroxymethyl-cyclopropyl)phosphonates by treatment with lithium diisopropylamide followed by addition of an aldehyde." Thus, typically, diethyl 2-hexylcyclopropylphosphonate gave diethyl 2-hexyl-l-[hydroxy(phenyl)methyl] cyclopropylphosphonate (19b) in 90% yield on reaction with benzaldehyde. ° Other electrophiles such as acetone, acetyl chloride, acetic anhydride, and ethyl acetate, were not sufficiently reactive to undergo addition to the anion. 

General Cyclopropanation Procedure 0.2 g chlorobenzene, 3 ml dichloromethane and 4 (0.490 g, 4.70 mmol) were added to the catalyst (1 mol% maximum Rh-loading) and the mbcture was stirred. Over a period of 3-5 hours a solution of 5a (0.0517 g, 0.453 mmol) or 5b (0.0599 g, 0.461 mmol) in 3 ml dichloromethane was added. After stirring overnight at room temperature (5a) or under reflux (5b), the solvent was evaporated in vacuo and the residue was chromatographed (silicagel, hexane/ethyl acetate 9/1). Before chiral GC analysis. 

The bisammine complexes are prepared by condensing dry ammonia at low temperatures onto I Oxygen ligands such as 1,4-dioxane, THF or DMF can be used as well. Simple alkylated cyclopropanes can be converted to the corresponding tetrameric platinacyclobutanes on reaction with chloroplatinic acid in ethyl acetate , rather than in acetic anhydride ... 

To a solution of the (pentenediyl)iron complex (0.12 g, 0.29 mmol) in DMF (15 mL) at room temperature solid CAN (1.75 g, 3.19 mmol) is added in one portion. The reaction mixture is stirred for 3 h, poured into water (20 mL), and extracted with dichloromethane (3 X 25 mL). The combined extracts are dried (magnesium sulfate) and the solvent is evaporated under reduced pressure. The residue is purified by chromatography (Si02, hexane-ethyl acetate [3 1]) to give the cyclopropane product as a translucent oil 44 mg (56%). 

Cyclopropyl sulfones were shown to be obtained either by cyclization of y-p-tosyloxy sulfones 232 with base or by treatment of phenylsulfonylacetonitrile 233a or ethyl phenyl sulfonyl acetate 233b with 1,2-dibromoethane in the presence of benzyltriethyl-ammonium chloride (BTEA) and alkali in good yields. Chang and Pinnick synthesized various cyclopropane derivatives 234 upon initial treatment of carbanions derived from cyclopropyl phenyl sulfone with either alkylating agents or a carbonyl compound and subsequent desulfonylation, as shown below. 

ETHYLENE GLYCOL ETHYL MERCAPTAN DIMETHYL SULPHIDE ETHYL AMINE DIMETHYL AMIDE MONOETHANOLAMINE ETHYLENEDIAMINE ACRYLONITRILE PROPADIENE METHYL ACETYLENE ACROLEIN ACRYLIC ACID VINYL FORMATE ALLYL CHLORIDE 1 2 3-TRICHLOROPROPANE PROPIONITRILE CYCLOPROPANE PROPYLENE 1 2-DICHLOROPROPANE ACETONE ALLYL ALCOHOL PROPIONALDEHYDE PROPYLENE OXIDE VINYL METHYL ETHER PROPIONIC ACID ETHYL FORMATE METHYL ACETATE PROPYL CHLORIDE ISOPROPYL CHLORIDE PROPANE... 

Considering the above-mentioned facts, according to which simple diazoketones yield dihydrofurans with ketene acetals but cyclopropanes with enol ethers, one exports an interlink between these clear-cut alternatives to exist, i.e. substrates from which both cyclopropanes and dihydrofurans result. In fact, providing an enol ether with a cation-stabilizing substituent in the a-position creates such a situation The Rh2(OAc)4-catalyzed decomposition of -diazoacetophenone in the presence of ethyl vinyl ether produces mainly cyclopropane 82 (R=H), but a small amount of dihydro-... 

The comparison between the cycloaddition behavior of simple diazoketones and of ethyl diazopyruvate 56 towards the same olefin underlines the crucial influence of the ethoxycarbonyl group attached to the carbonyl function. This becomes once again evident when COOEt is replaced by an acetal function, such as in l-diazo-3,3-di-methoxy-2-butanone 86 with enol ethers and acetates, cyclopropanes rather than dihydrofurans are now obtained 113). ... 

Palladium(II) acetate was found to be a good catalyst for such cyclopropanations with ethyl diazoacetate (Scheme 19) by analogy with the same transformation using diazomethane (see Sect. 2.1). The best yields were obtained with monosubstituted alkenes such as acrylic esters and methyl vinyl ketone (64-85 %), whereas they dropped to 10-30% for a,p-unsaturated carbonyl compounds bearing alkyl groups in a- or p-position such as ethyl crotonate, isophorone and methyl methacrylate 141). In none of these reactions was formation of carbene dimers observed. 7>ms-benzalaceto-phenone was cyclopropanated stereospecifically in about 50% yield PdCl2 and palladium(II) acetylacetonate were less efficient catalysts 34 >. Diazoketones may be used instead of diazoesters, as the cyclopropanation of acrylonitrile by diazoacenaph-thenone/Pd(OAc)2 (75 % yield) shows142). 

Allyl acetals154). Allyl ethers give no or only trace amounts of ylide-derived products in the Rh2(OAc)4-catalyzed reaction with ethyl diazoacetate, thus paralleling the reactivity of allyl chloride. In contrast, cyclopropanation must give way to the ylide route when allyl acetals are the substrates and ethyl diazoacetate or dimethyl diazomalonate the carbenoid precursors. 

The catalytic activity of rhodium diacetate compounds in the decomposition of diazo compounds was discovered by Teyssie in 1973 [12] for a reaction of ethyl diazoacetate with water, alcohols, and weak acids to give the carbene inserted alcohol, ether, or ester product. This was soon followed by cyclopropanation. Rhodium(II) acetates form stable dimeric complexes containing four bridging carboxylates and a rhodium-rhodium bond (Figure 17.8). 

Ethyl diazoacetate (22.8 g, 0.20 mol) is added at a rate of 1.5 mL h" to a stirred mixture of acrolein dimethyl acetal (40.8 g, 0,40 mol) and rhodium(Il) acetate (0.44 g, 0.001 mol, 0.5%), keeping the temperature of the reaction mixture at 20 °C. The mixture is then filtered through a short column of neutral alumina which is washed with ether. Distillation of the combined filtrates yields 19.2 g of a fraction (bp 107-112 °C, 13 Torr) consisting of 93% of the title compound (47% yield) and 7% of the cyclopropanation product. 

More recent reports from Cordova [155] and Wang [156] have described the cyclopropanation of a, P-unsaturated aldehydes 99 with diethyl bromomalonates 100 and 2-bromo ethyl acetoacetate catalysed by a series of diaryIprolinol derivatives. Both describe 30 as being the most efficient catalyst in many cases and optimal reaction conditions are similar. Some representative examples of this cyclopropanation are shown in Scheme 40. The transformation results in the formation of two new C-C bonds, a new quaternary carbon centre and a densely functionalised product ripe for further synthetic manipulation. Triethylamine or 2,6-lutidine are required as a stoichiometric additive in order to remove the HBr produced during the reaction sequence. The use of sodium acetate (4.0 equivalents) as an additive led to subsequent stereoselective ring opening of the cyclopropane to give a,P-unsaturated aldehydes 101. It can be envisioned that these highly functionalised materials may prove useful substrates in a variety of imin-ium ion or metal catalysed transformations. 

Wenkert and Khatuya (51) examined the competition between direct insertion of a carbene into furan (via cyclopropanation) and ylide formation with reactive side-chain functionality such as esters, aldehydes, and acetals. They demonstrated the ease of formation of aldehyde derived carbonyl ylides (Scheme 4.30) as opposed to reaction with the electron-rich olefin of the furan. Treatment of 3-furfural (136) with ethyl diazoacetate (EDA) and rhodium acetate led to formation of ylide 137, followed by trapping with a second molecule of furfural to give the acetal 138 as an equal mixture of isomers at the acetal hydrogen position. 

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