1,3-dicarbonyl compounds cyclopropanation

According to Scheme 1 methyl 2-siloxycyclopropanecarboxylates should also be available from donor-acceptor-substituted olefins like 100, which are easily synthesized by silylation of the corresponding 1,3-dicarbonyl compounds. Cyclopropanation of 100 with methyl diazoacetate or diazomethane could be realized in the presence of Cu(II)-catalysts, but due to the relatively low reactivity of the olefins a large excess of diazoalkanes had to be employed. This makes the isolation of 101 troublesome and therefore direct hydrolysis with acid to give 1,4-dicarbonyl compounds 102 is advantageous (Eq. 32) 66). 

The reductive cyclization of readily available enol phosphates of 1,3-dicarbonyl compounds bearing pendant olefinic units has been explored [66,67]. The chemistry is exceptionally interesting, and provides a unique route to structures possessing a cyclopropyl unit which is suitable for structural elaboration. The reaction occurs in a manner wherein the phosphate-bearing carbon behaves like a carbene that adds to the pendant alkene to form a cyclopropane. While this provides a useful way of viewing the transformation, mechanistic studies indicate that a carbene is not an actual intermediate. Examples are portrayed in Table 11. 

The initial product from reduction of aliphatic 1,3-dicarbonyl compounds is either a cyclopropane derivative formed by intramolecular condensation or a glycol... 

With a range of methods available for the formation of 1,3-dicarbonyl compounds, the dicarbonyl diazomethanes can be readily prepared via a simple diazo transfer reaction with sulfonyl azide. This has made a vast array of dicarbonyl diazomethanes available, which enhances the versatility in organic synthesis. A selection of examples from recent literature to illustrate the versatility of the cyclopropanation using dicarbonyl diazomethane in the construction of natural products as well as other biologically active compounds is described below. 

Some other methods to synthesize 1,4-dicarbonyl compounds via cyclopropane or cyclobutanone derivatives are given in sections 1.J3.1 and 1.13.2. 

Alkenylboron compounds cyclopropanations, 9, 181 haloetherification, 9, 182 hydrogenation and epoxidation, 9, 182 metal-catalyzed reactions, 9, 183 metallic reagent additions, 9, 182 via radical addition reactions, 9, 183 5-Alkenylboron compounds, cross-coupling reactions, 9, 208 Alkenyl complexes with cobalt, 7, 51 with copper, 2, 160, 2, 174 with Cp Re(CO) (alkene)3 , 5, 915-916 with dicarbonyl(cyclopentadienyl)hydridoirons, 6, 175 with gold, 2, 255... 

As early as 1938 Rambaud reported the first synthesis of a donor-acceptor-substituted cyclopropane — obtained by the addition/elimination path (0 (Scheme 1) — and he also recognized that these cyclopropanes are prone to ring cleavage providing 1,4-dicarbonyl compounds. After saponification 19 opens to 20 which is oxidized by air to the isolated succinic acid 219). 

Many combinations of substituents at the cyclopropane ring have been realized, but not all are of synthetic value. In this respect alkyl 2-siloxycyclopropanecarboxylates are of particular versatility. They allow many modes of ring cleavages which can be combined with change of functionality or with C-C-bond forming reactions providing a manifold of poly functional 1,4-dicarbonyl compounds, carbocycles, and heterocyclic systems as products. 

Dioxins behave as masked cis y-hydroxy enones and as such are an excellent source of y-lactones, notably in an enantio-enriched form <02JOC5307>. Treatment of the dioxin with an amine base results in rearrangement to 1,4-dicarbonyl compounds from which pyrroles and thiophenes are available in a one-pot synthesis <02TL3199>. Stabilised phosphonates add to 1,2-dioxins to yield diastereo-pure substituted cyclopropanes <02JOC3142>. 

The synthetic interest of the reaction is even broader since several functional groups in the substrate, such as C=C double bond, ether, halogen, ester, and amide groups (entries 6-10) can be present in the carbon skeleton. Chemose-lective cyclopropanation reactions involved the enone functionality in the presence of a saturated ketone group (Scheme 9). Recently, the reaction was applied to the conversion of 1,3-dicarbonyl compounds into 2-alkoxyalkenyl cyclopropanes (Scheme 10) [15]. These molecules having both vinylcyclopropane and enol ether moieties are supposed to be versatile synthetic intermediates. 

Generally, push-pull substituted cyclopropanes as 2-364 are flexible building blocks and represent an equivalent for 1,4-dicarbonyl compounds. They show a pronounced tendency to undergo ring opening [202]. 

Although it has been known since 1938 that alkoxy-substituted alkyl cyclopropanecar-boxylates can be opened to 1,4-dicarbonyl compounds it was not until 1970 that the synthetic merit of this route to a valuable class of intermediates was recognized. In this year Wenkert and coworkers described the preparation of cyclopentenones from this type of cyclopropane via 1,4-diketones as outlined in equation 83 " . Shortly later McMurry and Glass have published a ds-jasmone synthesis following the same principle ... 

Another approach to acceptor-substituted siloxycyclopropanes has recently been described Here, a 1,3-dicarbonyl compound is converted to the corresponding p-trimethylsiloxy a, ) -unsaturated ketone or ester. Cyclopropanation and ring-opening gives 1,4-dicarbonyl compounds, however, conversions and yields are moderate. 

The carbenoid reaction between a-diazo ketones and simple alkenes or styrenes leads to acylcyclopropanes. (For the enantioselective cyclopropanation of styrene with 2-diazo-5,5-dimethylcyclohexane-l,3-dione, see Section 1.2.1.2.4.2.6.3.2.). With ketene acetals, 2,3-dihyd-rofurans are obtained. In contrast, l-acyl-2-oxycyclopropanes or 2-oxy-2,3-dihydrofurans can be formed in reactions with enol ethers and enol acetates the result depends strongly on the substitution pattern of both reaction partners.Whereas simple diazo ketones usually lead to cyclopropanes (Table 15), 3-diazo-2-oxopropanoates and 2-diazo-l,3-dicarbonyl compounds, such as 2-diazoacetoacetates, 3-diazopentane-2,4-dione, and 2-diazo-5,5-dimethylcy-clohexane-1,3-dione, yield 2,3-dihydrofurans and occasionally acyclic structural isomers thereof when reacted with these electron-rich oxy-substituted alkenes. 

Diazomalonic esters, in their behavior towards enol ethers, fit neither into the general reactivity pattern of 2-diazo-l,3-dicarbonyl compounds nor into that of alkyl diazoacetates. With the enol ethers in Scheme 17, no dihydrofurans are obtained as was the case with 2-diazo-l,3-dicarbonyl compounds. Rather, copper-induced cyclopropanation yielding 70 occurs with ethoxymethylene cyclohexane However,... 

Reproduced with permission from Wang G-W, Gao J. Selective formation of Spiro dihydrofurans and cyclopropanes through unexpected reaction of aldehydes with 1,3-dicarbonyl compounds. Org Lett 2009 11 2385-8. Copyright (2009), American Chemical Society. 

Condensation of the enol ethers of P-dicarbonyl compounds with dimethylsul-phonium methylide generally takes place by attack on the carbonyl group, leading to furans. However, enol ethers derived from P-keto-aldehydes are attacked first at the double bond to give cyclopropanes. These further react at the carbonyl group, the resulting cyclopropyl epoxides rearranging to dihydropyrans (Scheme 1). 

In an electrochemical synthesis of cyclopropanes, the mesylates of 1,3-diols, which are readily available via the 1,3-dicarbonyl compounds, can be cyclized in good yield. Similarly, 1,3-di-iodides are cyclized to cyclopropanes by treatment with t-butyl-lithium. An excellent precursor to three-membered rings is 3-(tri-n-butylstannyl)propanal (5), by extension of the aldehyde to an enone (6)... 

The title compound also exhibits affinity for /3-dicarbonyl compounds, enabling their use as leaving groups in retro-Claisen reactions (eq 29) or cyclopropane-1,1-diester ring openings. ... 

---