Reduction of cyclopropyl ketone

The reductive opening of a cyclopropane ring of a conjugated cyclopropyl ketone with lithium in liquid ammonia can be viewed as an overall two electrons reduction which yields the equivalent of a carbanion and an enolate ion (cf. 237). Successive protonations of 237 then gives the reduced ketone. 

Norin (71) and Dauben and collaborators (72-74) have shown that the bond of the cyclopropane ring which is reductively cleaved corresponds to the bond which better overlaps with the u system of the adjacent carbonyl group. Thus, when the cyclopropyl ketone exists preferentially in the cisotd and transoTd conformations described by the Newman projections 238 and 239, the C- —C2 bond is always cleaved in preference to the C3 bond. 

A few representative examples will be reported here. The reduction of lumi-cholesterone (240) with lithium in liquid ammonia gives the spiroketone 2  

X system of the carbonyl groups is cleaved. Norin (71) as well as Dauben and Deviny (72) have reported the reduction of ( )-carone (242) into 243. 

Dauben and Wolf (73) have also studied the chemical reduction of a series of acyclic cyclopropyl ketones 1252-254) with lithium in liquid ammonia. 

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Since the cyclopropyl ring mimics the C=C double bond in several processes, most controlled potential electrochemical reductions of cyclopropyl ketones are compared with those of a,) -unsaturated ketones. Polarographic study revealed " that the Ei /2 for the former (Table 8) is in between that of saturated ketones and of a,) -unsaturated ketones. This indicates a possible interaction of the cyclopropyl ring with the carbonyl group. A general mechanism for the electrochemical reduction of cyclopropyl ketones may be outlined as follows. Mandell and coworkers reduced electrochemically two cyclopropyl... 

A number of intermediates related to the cyclopropylmethyl radical undergo rapid ring opening. 1-Cyclopropylvinyl radicals 35 rearrange to 2-(allenyl)ethyl radicals 36, while radical anions 37, formed by one-electron reduction of cyclopropyl ketones, ring open to give enolate radicals... 

Section 1.1.1.3.1.1.2.1.). Similarly, the reductive ring opening of cyclopropyl ketones, e.g., 8, with lithium in ammonia affords specific enolates20,21. These enolates can, of course, be used for selective alkylation. Furthermore, enol acetates, e.g., 10, are regiospecifically obtained by nucleophilic ring opening of cyclopropyl ketones21. 

Cleavage of cyclopropyl ketones.8 Cyclopropyl ketones are converted by lSi(CH3)3 under very mild conditions into y-iodo ketones. The regioselectivity is usually high and is similar to that observed in lithium-ammonia reductions. 

The method is a modification of one used by Barton and McCombie.8 Reduction of ketones.9 Ketones can be reduced to alcohols by Bu3SnH in the presence of either AIBN or a Lewis acid, but this reaction is limited to unhindered ketones. However, even sterically hindered ketones, such as f-butyl methyl ketone, can be reduced under high pressure (10 kbar) in the absence of a catalyst. This method is particularly useful in the case of cyclopropyl and a,p-epoxy ketones, which are reduced to the corresponding alcohols. Reduction of these ketones with Bu3SnH under radical conditions results in ring-opened products. 

This section covers the reduction of aldehydes and ketones, in complex molecules using hydride transfer reagents. Many of these are complex reagents designed specifically for particular reactions. LAH has been used for the reduction of cyclopropyl ketones199. Trialkyltin moieties in the cyclopropane ring cause diastereoselective reduction to occur (equation 51). 

Additional support for an alternative alkene first mechanism in these cyclisations came from the successful cyclisation of cyclopropyl ketone 26 with no observance of fragmentation products (Scheme 5.21).43 This suggests that a ketyl radical anion is not formed during the cyclisation and that reduction of the alkene leads to product formation. 

TABLE 8. Reduction potentials of cyclopropyl ketones and related derivatives... 

The hydrostannation of carbonyl compounds to give alkoxystannanes (equation 14-5) can follow a homolytic or heterolytic mechanism depending on the structure of the reactants and on the reaction conditions (Section 20.1.3). This existence of alternative mechanisms is elegantly demonstrated in the reduction of cyclopropyl methyl ketone by tributyltin hydride. In methanol, 1-cyclopropylethanol is formed in a polar process, but, with irradiation with UV light, the main product is pentan-2-one, which is formed by ring opening of the cyclopropylmethyl radical by P-scission (Scheme 14-1)14... 

Aldehydes or ketones containing a cyclopropyl group adjacent to the carbonyl group can be converted to ring-opened carbonyl compounds by several different types of two-electron reduction processes. The most widely used method employs lithium metal in liquid ammonia as the reductant. The cyclopropyl ketone is usually dissolved in anhydrous diethyl ether and added to the blue metal-ammonia solution. Occasionally, the order of addition is reversed, and the lithium is added to a solution of the ketone in ammonia and diethyl ether. After a timed interval, the reduction is quenched by adding solid ammonium chloride to give a mixture of alcohols and ketones. This mixture is generally oxidized before isolation, with chromium(VI) oxide/pyridine or with sodium dichromate/sulfuric acid, to solely afford the ketone. 

A different method of reductive cleavage was developed which employed photolysis of cyclopropyl ketones in a hydrogen donor solvent, usually isopropyl alcohol.This photoreduction gave rearranged ketones and alcohols which were routinely oxidized, as in the lithium/ ammonia process. 

The alcohol dehydrogenase from Thermoanaerobium brockii is very suitable for the reduction of aliphatic ketones[18, 19L Even very simple aliphatic ketones can be reduced enantioselectively. An interesting substrate size-induced reversal of enantio-selectivity was observed. The smaller substrates (methyl ethyl, methyl isopropyl or methyl cyclopropyl ketones) were reduced to the (R)-alcohols, whereas higher ketones produced the (S -enantiomers. 

Reduction of cyclopropyl methyl ketone has been attempted by four different methods 415 Only poor yields of the alcohol were obtained by use of sodium and alcohol on use of LiAlH4 difficulties were encountered for larger batches and catalytic hydrogenation with Raney nickel caused partial cleavage of the cyclopropane ring however, excellent yields of 1-cyclopropylethanol were obtained in the presence of a copper-chromium oxide catalyst activated by barium, at 100°. 

Modhephene, 34, was the first isolated propellane natural product. As such, the Weiss-Cook reaction was the perfect method for its construction. The process began with the condensation of 2 with diketone 27. Standard conditions for decarboxylation produced the core scaffold 28. Hydrogenation of the mono-enol phosphate afforded the monoketone 29. The cyclopropyl derivative 30 was prepared by copper-catalyzed decomposition of a diazoketone. gem-Dimethylation to generate 31 preceded carboxylation and esterification to afford the advanced intermediate 32. Cuprate-induced cyclopropane ring opening and methylation of the 3-ketoester introduced the final carbon atoms giving rise to 33. Lithium iodide induced decarboxylation preceded reduction of the ketone followed by dehydration with Martin s sulfurane, thus producing 34. 

Palladium-catalyzed ring-opening hydrosilylation of cyclopropyl ketones formed (Z)-enol silanes (Scheme 2.79) [131]. The mechanism is proposed to proceed via oxidative cyclization, ring contraction, transmetalation, and reductive elimination. In contrast, the rhodium-catalyzed reaction afforded mixtures of cyclopropanes and ring-opened products [132]. 

Treatment of oc-cyclopropyl ketones with lithium in a mixture of N,N-d2 propylamine and hexamethylphosphortriamide is a recently reported method for deuterium labeling via reductive ring opening. This reaction provides y-labeled ketones in good yield (70-100%) and isotopic purity (85-93%). 

Cyclopropanes can be cleaved by catalytic hydrogenolysis. Among the catalysts used have been Ni, Pd, and Pt. The reaction can often be run under mild condi-tions." ° Certain cyclopropane rings, especially cyclopropyl ketones and aryl-substituted cyclopropanes," can be reductively cleaved by an alkali metal (generally Na or Li) in liquid anunonia." Similar reduction has been accomplished photo-chemically in the presence of LiC104." ... 

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