Methylene cyclopropyl ketone

Kilburn s sequential approach, the six- and five-membered rings of the target are generated stereoselectively in one synthetic operation. Treatment of methylene-cyclopropyl ketone 1 with Sml2, in the presence of HMPA and t-BuOH, gave the bicyclic ether 2 as a 10 1 mixture of diastereoisomers (Scheme 6.1). 

Representative procedure. To freshly prepared Sml2 (2.2 equiv, 0.15 M in THF) HMPA (21.4 equiv) was added and the solution was cooled to 0°C. Methylene-cyclopropyl ketone 1 (1 equiv) and t-BuOH (2 equiv) as a solution in THF were added to the reaction mixture dropwise over 90 min. The reaction mixture was allowed to warm to room temperature before quenching with 5% aqueous citric acid and extracting into petroleum ether-EtOAc (1 1). The organic layers were washed with brine, dried (MgS04) and concentrated in vacuo. Crude 2 was purified by column chromatography (petroleum ether-EtOAc). 

Along the same lines, Kilburn and coworkers have shown that BF3 AcOH, a mild Lewis acid, is able to promote the cascade cyclization of trimethylsilyl-substituted methylene cyclopropyl ketone (146) to afford the oxabicyclic compound (147) through the intermediacy of the allyl cation (148) (Equation 88) [90]. 

A single product is also formed in the case of unsymmetrical ketones of the MeCOCHR R2 or RCH2COCHR R2 type, since for the Pfitzinger reaction to occur the ketone must contain either a methyl group or a methylene group next to the carbonyl group. For example, only one appropriate cyclopropyl-substituted acid 16 is formed from methyl cyclopropyl ketone 15 and isatins 9 [23, 24],... 

Further activation and functionality is introduced to cyclopropyl ketones or esters by an additional hydroxymethyl substituent or its equivalent. On this basis, a synthesis of a-methylene y-butyrolactones has been performed (equation 52). ... 

Methylene transfer from isopropylidenetriphenyl-l -phosphane to a,/i-unsaturated esters allows the preparation of gew-dimethyl-substituted cyclopropyl ketones, e.g. The ketones... 

A methodically related transformation, the copper(Il)-mediated transfer of a cyano(ethoxycar-bonyl)methylene unit from ethyl cyanoacetate to alkenes, is presented in Section I.2.I.2.4.2.9. The copper-mediated synthesis of cyclopropyl ketones from a,a-dibromo ketones and alkenes seems to be of very limited scope and even less efficient than the corresponding synthesis of cyclopropanecarboxylic acids from o ,a-dibromoacetates (vide supra). The reaction (toluene, 100°C, 93 h) of cyclooctene (4.0 mmol), dibromomethyl phenyl ketone (8.0mmol), and commercial grade copper powder (18 mmol) activated with iodine (0.2 mmol) gave exy-9-benzoyl-bicyclo[6.1.0]nonane (7, 12%) and (2-oxo-2-phenylethyl)cyclooct-l-ene (8, 3%). ° A similar treatment of styrene gave l-benzoyl-2-phenylcyclopropane in only 2% yield [ratio (cisjtrans) 1 l.b]. " ... 

Oxatrimethylenemethanepalladium complexes can also be generated by oxidative addition of palladium(O) to 5-methylene-l,3-dioxolan-2-ones and subsequent decarboxylation. Again, reaction with norbornene, norbornadiene and dicyclopentadiene yields polycyclic cyclopropyl ketones in medium to high yield (Table 19). In this case, tetrakis(triphenylphosphane)pal-ladium(O) was the best catalyst found, whereas tris(dibenzylideneacetone)palladium(0)-chloro-form/triphenylphosphane (see above) and bis(cycloocta-l,5-diene)nickel/triphenylphosphane (used in stoichiometric amounts) proved less efficient. 

Cyclopropyl ketones. Methylene groups attached to a cyclopropane ring are nidized. 

Two papers report the synthesis of novel androstane derivatives methylated at C-8a. In the first" (Scheme 8). treatment of the tosylhydrazone of (143) with lithium hydride furnished the diene (144). Reaction with diborane. followed by alkaline hydrogen peroxide, gave the allylic alcohol (145), which was submitted to Simmons-Smith reaction and oxidized to the a-cyclopropyl ketone (146). Cleavage of the 7a.8a-methylene bridge with lithium in liquid ammonia afforded the 8a-methyl derivative (147). This was then converted into 17a-ethynyl-8a-methyltestosterone (148a) by a classical sequence of reactions. ... 

An effort was made to prepare a butyl analogue containing a ring, but it was never completed. This was the cyclopropylmethyl isomer, 2,5-dimethoxy-4-cyclo-propylmethylamphetamine hydrochloride, DOCPM. Only the first step of its synthesis was complete (the reaction of cyclopropylcarboxylic acid chloride with p-dimethoxybenzene) and even it went badly. The desired ketone (2,5-dimethoxyphenyl cyclopropyl ketone) was most difficult to separate from the recovered starting ether. A promising approach would be the isolation of the phenol (2-hydroxy-5-methoxyphenyl cyclopropyl ketone) which is a beautiful yellow solid with a melting point of 99-100 °C from methanol. Anal. (Cl 1 HI203) C,H. It then could be methylated to the wanted intermediate. It is the major product when the reaction is conducted with anhydrous aluminum chloride in methylene chloride. 

Beside carbenes and carbenoids, metal-catalyzed cyclopropanation using other types of intermediate is also feasible. Treatment of 5-methyl-5-phenyl-4-methylene-l,3-dioxolan-2-one with palladium(O) catalyst in the presence of norbomene produced the cyclopropyl ketone in excellent yield (Scheme 8) (60). The active intermediate was proposed to be a Zwitterion... 

Even cyclopropanes lacking a methylene or vinyl group can be involved in formal cycloadditions. Cyclopropyl ketones 11.137 undergo cycloaddition to enones under nickel catalysis with an NHC ligand (Scheme 11.47) in the absence of the enone, their dimerization is observed. The reaction is proposed to proceed via a metallacyclic enolate complex 11.140, perhaps after initial oxidative addition to one of the cyclopropyl C-C bonds. 

A mixture of senecioic acid chloride, AICI3, and methylene chloride added drop-wise at -60° to a stirred soln. of 3-methyl-l-trimethylsilylbut-2-ene in methylene chloride, kept 10 min. at -60°, then poured slowly on a mixture of NH4CI and ice artemisia ketone. Y 90%, J. P. Pillot, J. Dunogues, and R. Galas, Tetrah. Let. J976, 1871 cyclopropyl ketones from cyclopropylsilanes s. Synthesis 1976, 737 syntheses with 3-trimethylsilylcyclopentene s. J. Ojima, M. Kumagai, and Y. Miyazawa, Tetrah. Let. 1977, 1385. 

Attempts at making epoxycyclopropanes (595) from a -unsaturated ketones and cyclopropyl ketones with ylide methylene-transfer reagents have been reported. " However, compounds were isolated which are believed to be products of rearrangement of the unisolable epoxycyclopropanes. 

SnCU is also effective in the opening of cyclopropane rings to produce cationic intermediates useful in cyclization reactions. For example, the cyclization of aryl cyclopropyl ketones to form aryl tetralones, precursors of aryl lignan lactones and aryl naphthalene lignans, is mediated by SnCU (eq 24). The reaction is successful in nitromethane, but not in benzene or methylene chloride. Analogous cyclizations with epoxides result in very low yields (2-5%). 

Dibromoethane normally reacts with activated methylene groups to produce cyclopropyl derivatives [e.g. 25, 27], but not with 1,3-diphenylpropanone. Unlike the corresponding reaction of 1,3-dibromopropane with the ketone to form 2,6-diphenylcyclohexanone, 1,2-dibromoethane produces 2-benzylidene-3-phenyl-tetrahydrofuran and the isomeric 2-benzyl-3-phenyl-4,5-dihydrofuran via initial C-alkylation followed by ring closure onto the carbonyl oxygen atom (Scheme 6.2) [28],... 

The BH.i/BF.vOEt2 reagent reduces not only aryl ketones and aldehydes, but also cyclopropyl aryl or dicyclopropyl ketones to the methylene compounds without opening or rearrangement in the cyclopropyl unit (equation 21). ... 

Cyclopropyl phenyl ketone afforded quantitatively n-butylbenzene, instead of cyclopropylphenylme-thane, because of the reactivity of the cyclopropyl group. In the case of 6-methoxytetralone, a dehydrogenation product (50) was obtained in 20% yield together with the desired methylene compound (51) in 33% yield (equation 26). Because the tetraline structure of (51) can be a hydrogen donor, the newly formed product (51) may be consumed during the reaction hence the formation of the naphthalene (50). ... 

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