Cyclobutanones => cyclopropyl

The ambivalent aptitude of sulfur [19] to stabilize adjacent anionic as well as cationic centers is a remarkable fact that has shown to be a reliable feature for the assembly of four-membered ring scaffolds utilizing cyclopropyl phenyl sulfides [20]. Witulski and coworkers treated the sulfide 1-69 with TsOH in wet benzene (Scheme 1.19) [21]. However, in addition to the expected cyclobutanone derivative 1-70, the bicyclo[3.2.0]heptane 1-70 was also obtained as a single diastereoisomer, but in moderate yield. Much better yields of 1-71 were obtained using ketone 1-72... 

This chapter begins by classifying the combinations of oxidation/reduction processes with subsequent cationic transformations, though to date the details of only two examples have been published. The first example comprises an asymmetric epoxidation/ring expansion domino process of aryl-substituted cyclopropyl-idenes (e. g., 7-1) to provide chiral cyclobutanones 7-3 via 7-2, which was first described by Fukumoto and coworkers (Scheme 7.1) [2]. 

As invented by Wender,196,197 a variant of the second transformation can take place if the alkene partner is substituted by a participating group such as a strained cyclopropyl or a cyclobutanone (in the case of a 1,6-diene).198 The whole process, which mainly relies on the use of rhodium or ruthenium complexes,1 9 results in the formal... 

Substituted cyclopropyl ylides also participate in oxaspiropentane formation (Table 2, entries 4d, 30b, 38, and 39). Of the two cyclopropyl carbons that can move in the rearrangement to cyclobutanones, the carbon that best stabilizes a... 

These electrophilic conjunctive reagents require donor reactants. The cyclopropyl-carbinols as precursors to cyclobutanones arise by simple addition of organometallics. For example, the cyclobutanone 47 derives by addition of vinyllithium to 44 followed by rearrangement with aqueous fluoroboric acid 92). In some cases, this route to cyclopropylcarbinols is preferred. Addition of 41 to aldehydes or ketones... 

The availability of cyclopentenones from butanolides allows the lactone annulation to facilitate the synthesis of cyclopentyl natural and unnatural products. An example that highlights the latter is dodecahedrane (178) for which 179 constitutes a critical synthetic intermediate 136,137). Lateral fusion of cyclopentenones as present in 179 can arise by acid induced reorganization and dehydration of 180. While a variety of routes can be envisioned to convert a ketone such as 182 into 180, none worked satisfactorily137 On the other hand, the cyclobutanone spiro-annulation approach via 181 proceeds in 64 % overall yield. Thus, the total carbon cource of dodecahedrane derives from two building blocks — cyclopentadiene and the cyclopropyl sulfonium ylide. 

This type of cyclobutanone annelation is feasible with various dibromocyclopropanes. When diaryl ketones are used as electrophiles, the oxaspiropentane-cyclobutanone rearrangement occurs spontaneously, so that the cyclobutanone is obtained directly (equation 63)"° . When 1-bromo-l-lithiocyclopropanes are allowed to react with aldehydes, the formation of cyclopropyl ketones results" . 

Only a few examples exist where diazocyclopropane has been used for annulations via oxa-spiropentanes. 1,3-Bisdiazopropane reacted with cyclohexanone, probably by previous formation of diazocyclopropane, to give spiro[2.6]nonan-4-one (2, 27%) and spiro[3.5]nonan-l-one (1, 10%).82 83 The latter was formed from the corresponding oxaspiropentane.83 Diazocyclopropane, as generated from /V-cyclopropyl-iV-nitrosourea or /V-cyclopropyl-iV-nitrosocarba-mate, behaves similarly. It reacts with cyclobutanone to give spiro[2.4]heptan-4-one (4, 80%) and spiro[3.3]heptan-l-one (3, 7%).84... 

Donor-substituted 1-aminomethylcyclopropanes 108 110 and tosylhydrazones of 1-donor-substituted cyclopropyl ketones 111 can undergo ring enlargement to cyclobutanones through deamination. To this purpose, aminomethylcyclopropanes were diazotized with sodium nitrite 108-110 or isopentyl nitrite 109 in acidic medium and tosylhydrazones were decomposed in basic medium.111 The rearrangements proceed via diazonium ions and are especially useful for the construction of bicyclic systems. For examples of these rearrangements see 1,108 2,109 3,109 4,110 5,111 6 and 7.1 1... 

To a solution of A -[l-(hydroxymethyl)cyclopropyl]formamide 9 (200 mg) in CHCI, was added a few drops of 45% BF3 Oht2 in Lit,0 and the mixture was heated under reflux for 30 min. After addition of H,0 the mixture was extracted with CH2C12 and the extract concentrated to give the crude cyclobutanone in > 80% yield. 

Chiral 2,2-disubstituted cyclobutanones have been obtained by asymmetric rearrangement of chiral sulfinyl- 177,178 and sulfanylcyclopropanes.179 Using readily available cyclopropyl 4-tolyl (/ )-sulfoxide (l),180 the requisite sulfinylcyclopropanes 3 and 3 were obtained by a sequence of lithiation, reaction with carboxylic acid esters and stereoselective addition of Grignard reagents to the ketones 2 thus formed.178 The corresponding sulfanylcyclopropanes 4 and 4 resulted from a sequence of protection, reduction and deprotection.179... 

Treatment of a-cyclopropyl acyl silanes with sulphuric or triflic acids results in rearrangements to give cyclobutanones and 2-silyl-4,5-dihydrofurans, respectively, in processes formally involving intramolecular nucleophilic attack at the acyl silane moiety (Scheme 80)190. 

The first recorded cyclopropyl acyl silane (69) was generated by vapour phase pyrolysis of a pyrazoline derived from a,/)-unsaturated acyl silane by 1,3-dipolar cycloaddition of diazomethane (vide supra, Section DTE)141. Exposure of 69 to titanium tetrachloride induced ring expansion to give the cyclobutanone in 75% yield (Scheme 113). 

Alkylation reactions which introduce a double bond adjacent to the cyclopropane ring provide intermediates which may undergo useful rearrangements to the cyclobutanone system. As shown in Scheme 20, reactions of 1-vinylcyclopropanol (108) with acid, positive halogens, peracids or carbonium ions lead to cyclobutanones via the cyclopropyl carbinyl cation 109. 76>... 

Moreover, removal of ether under vacuum and addition of tetrahydrofuran to the crude mixture of tosylates 229 and LiCl effected the ring expansion to cyclobutanones 230 and cyclobutenyl ethers 231. Upon treatment with anhydrous zinc bromide in methylene chloride, enol ethers 231 also underwent cleavage to give the expected cyclobutanones 230. In this way 2-alkynylcyclobutanones 230 with different substituents on the triple bond (i.e., R = CH3, C6H5, cyclopropyl, etc.) were obtained in 55-60% yield 110). It was obvious from these experiments that LiCl in THF was effective to cleave the MEM ethers 228, while MEM ethers usually require zinc-bromide 103-104), and induce their ring expansion. This likely involves, after ionization of the tosylates in THF, the intermediacy of the cyclobutyl cyclopropylcarbinyl carbenium ion system 232 U0). 

Since thiophenol was formed in the reaction, this by-product trapped the intermediate cation to give the bis(phenylthio)vinylcyclopropane 244 and so limited the formation of the desired cyclobutanone. To overcome this problem, a substitution pattern providing electronic acceleration for the cyclopropyl bond migration but also a steric bulk to inhibit the nucleophilicity of the thiol was required. For this purpose, l-(2,6-di-methoxyphenylthio)vinylcyclopropanes such as 242b were prepared the yield and cleanliness of the reaction were effectively increased, allowing by this route the isolation of pure cyclobutanones 243 63). 

Triple-bond participation has been mainly studied (by Hanack and his school) in reactions of homopropargyl derivatives 31 under solvolytic conditions. In all cases of Table 3, except 1 and 2, compounds 31 yield, besides (and very often instead of) the expected solvolysis products, cyclobutanone derivatives (32) and alkyl cyclopropyl ketones (33). 

The relative yields of cyclized products increase greatly with the decreasing nucleophilicity (2a-c, 3 and 4 of Table 3) and with the increasing ionizing power of the solvent. Cyclobutanone derivatives (32) are usually obtained in much greater amounts than cyclopropyl ketones (33) but, when mercuric ions are added, formation of 33 is overwhelming. The effect of R in 31 on the product distribution is illustrated in cases 3b, 4a, 5a, 6a, and 7. 

Only rearranged cyclobutanones were obtained in the case of benzophenone and cyclopropyl methyl ketone. 

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