Cyclization reactions cyclobutanones

The formation of cyclobutanones has been reported by Nawar and Le Tellier (1972 Le Tellier and Nawar, 1972a) and Dubravcic (1968). The cyclization reaction (Scheme 7.1) produces characteristic cyclobutanones derived from the fatty acids of the lipid. In recent years, as well as the well-known 2-dodecylcyclobutanone, 2-tetradecylcyclobutanone, 2-tetrade-cenylcyclobutanone and 2-tetradecadienylcyclobutanone have been found and synthesized in irradiated lipids, so the cyclization products of all main fatty acids has been observed. All the products are widely used to identify irradiated foodstuffs and to estimate the applied dose. 

This method for the preparation of cyclobutanone via oxaspiropentane is an adaptation of that described by Salaiin and Conia. The previously known large-scale preparations of cyclobutanone consist of the reaction of the hazardous diazomethane with ketene, the oxidative degradation or the ozonization in presence of pjrridine of methylenecyclobutane prepared from pentaerythritol, or the recently reported dithiane method of Corey and Seebach, which has the disadvantage of producing an aqueous solution of the highly water-soluble cyclobutanone. A procedure involving the solvolytic cyclization of 3-butyn-l-yl trifluoro-methanesulfonate is described in Org. Syn., 54, 84 (1974). 

Intermolecular coupling of ketones and alkenes, promoted by SmH, occurs with excellent stereochemical control. In one such reaction, samarium(II) iodide has been used to prepare cyclobutanones and cyclobutanols from chiral, 6-oxohex-2-enoates (equation 137)520. The reaction is performed in THF in the presence of HMPT and occurs in good yield with excellent stereocontrol. If appropriately located carbonyl and alkene moieties are present in a molecule, then Sml2-HMPT can be used to form cyclooctanols by a radical cyclization process in some cases there is a reasonable degree of diastereoselectivity (equation 138)521,522. 

A synthetic method for the prepararation of cyclobutanones via an intramolecular cyclization of a ketone enolate has been reported.83 Enol triflates having a silyloxy group at the ft-position under the influence of TBAF give a cyclobutanone or a four-membered enol ether through rearrangement of the trifluoromethanesulfonyl group followed by an intramolecular C- or O-alkylation reaction (Scheme 49). 

The photochemical behavior of cyclobutanone (IS) contrasts sharply with that of other ketones. Cyclobutanone undergoes a cleavage also from the (n, r ) state, with subsequent fragmentation to ketene and olefin, decarbonylation to cyclopropane or cyclization to oxacarbene (16), whose concerted formation has also been proposed on the basis of stereochemical observations (Stohrer et al., 1974). In contrast, cyclohexanone cleaves exclusively from the triplet state and undergoes disproportionation reactions. The photochemical activity of cyclobutanone persists even at low temperatures (77 K) where cyclohexanone is photostable. 

In the two separate, initial reports on the reactivity of Fischer carbenes with enynes, one study found cyclobutanone and furan products [59], while the other found products due to olefin metathesis [60]. These products have turned out to be the exceptions rather than the rule, as enynes have since been found to react with Fischer carbenes to produce bicyclic cyclopropanes quite generally. The proposed mechanistic pathway is included as part of Bq. (28), in which vinylcarbene 10, produced by insertion of the alkyne into the metal carbene, may then cyclize with the pendant olefin to metallacyclobutane 11, leading to product. The first reported version of this reaction suffered from extreme sensitivity to olefin substitution [Eq. (28) compare R=H, Me] often producing side-products due to metathesis (through 11 to yield dienes) and CO insertion (into 10 to yield cyclobutanones and furans) [61]. Since then, several important modifications have been developed which improve yield, provide greater tolerance for alkene substitution, and increase chemoselectivity for the bicyclic cyclopropane... 

Radical ring expansion of fused cyclobutanones This reaction involves reaction of an ru-bromoalkylchloroketene with an alkene to form a cyclobutanone with an exo side chain. Treatment of this adduct with BuaSnH (AIBN) generates a radical that cyclizes to a ring annelated product because of relief of strain in the four-membered ring. This reaction can be used to append 7-, 8-, or higher-membered rings to appropriate alkenes. 

Cyclobutanone alkyl silyl acetals, obtained from [2-f2] cycloadditions, can be deprotected with 1 equiv of TBAF in THF to give the open-chain cyano esters in excellent yields (eq 5). When 4-chloro-2-cyanocyclobutane alkyl silyl acetals are used as substrates for this reaction, ( 7Z) mixtures of 2-cyanocycloprop-anecarboxylates are obtained by an intramolecular cyclization (eq 6). 

In addition to the preceding processes that involve cycloadditions in direct analogy to Diels-Alder-type processes, several formal [4+2] cycloaddition processes have been described that proceed via completely different substrate classes and reaction pathways. In one example, a novel two-carbon ring expansion process was reported by Murakami, wherein the addition of cyclobutanones with alkynes provides cyclohexenones by two-carbon ring expansion of the starting material (Scheme 3-23). The mechanism of this process likely involves oxidative cyclization of die ketone and alkyne with Ni(0) to provide a five-membered metallacycle, followed by a ringexpanding p-carbon elimination as key steps of the process. 

The cyclobutanol (357) and the cyclobutanone (358) are both converted into the lactone (359) on chromic acid oxidation in either aqueous or aqueous acetic acid medium. " Other alkylated cyclobutanols and cyclobutanones behave similarly. Yields vary between 55 and 90% depending on the specific case. The regioselectivity of the reaction is the same as that in the Baeyer-Villiger reaction. Direct oxidation with chromic acid of the cyclobutanol (360), formed by photochemical cyclization of the ketone (361), gives the 1,4-dione (362) in 55% yield. This is a considerable improvement in terms of both time and yield over the previously used sequence of dehydration and cleavage. 

With Ni° as a catalyst, an intermolecular [4+2] cycloaddition [45] reaction with cyclobutanone 52 and 4-octyne 53a produced cyclohexenone 54a in 95% yield. The proposed reaction mechanism is illustrated in Scheme 9. Presumably the reaction of 52 and 53a with Ni° would proceed through oxidative cyclization to give oxanicke-lacyclopentene (55). P-C elimination cleaves the cyclobutane ring to generate 56 and leads to formation of product 54a after reductive elimination. Overall, a formal [4+2] cycloaddition was accomplished with Ni° via p-C elimination. In contrast, Rh was not an effective catalyst for this transformation. 

In an extension of previous work, it has been found that Pd(0)-catalysed intramolecular cyclization of allylic acetates (21) can be used to prepare the chrysanthemic acid analogues (22). The potentially useful cw-cyclopropane (23) can be simply obtained by base-induced addition of cyanoacetate to ethyl 2-bromo-3,3-dimethylacrylate followed by decarboxylation oddly, a similar reaction using malonate fails to give a cyclopropane. Optically pure dichloro cw-chrysanthemic acid (26) has been obtained by a Favorskii rearrangement of the chiral cyclobutanone (25) prepared from the keten (24) by sequential [2 + 2]cycloaddition, cine-rearrangement, and resolution (Scheme 3). ... 

One of the principal problems in the synthesis of cyclobutene compounds is the isolation process, because of the general instability of the final products. As a result, cyclobutanones are isolated via gold(I)-catalyzed cyclization of 1,6-ene-ynamides II-4 (Scheme 3.4) [9, 10]. The formation of cyclobutene intermediate II-5 only takes place if the ynamides are terminal or substituted by a trimethysilyl group (R = H, TMS). Skeletal rearrangement products were also obtained as minor products. Conversely, in the reaction of the same substrates catalyzed by PtCl2, the 1,3-dienes were isolated as the major products in good yields [11, 12]. 

The rhodium-catalyzed successive C-C/C-O bond cleavage reaction of a cyclobutanone 77 containing a phenoxymethyl side chain was affected by the employed bidentate diphosphine ligand (Scheme 3.44) [53]. In the presence of [Rh(nbd)(dppe)]PF 5 (nbd, norborna-2,5-diene dppe, l,2-bis(diphenylphos-phino)ethane) (5 mol%) and diphenylacetylene (20 mol%), cyclobutanone 77 was transformed into the alkenoic ester 78 in 88% yield via C-C bond cleavage, P-oxygen elimination, and reductive elimination. In contrast, the [Rh(nbd)(dppp)]PFg-catalyzed (dppp, l,3-bis(diphenylphosphino)propane) reaction afforded cyclopentanone 79 in 81% yield through a rhodacyclohexanone species that was formed by 6-endo cyclization. The reaction of the cyclobutanone 77 catalyzed by [Rh(nbd)(dppb)]PFg (dppb, l,4-bis(diphenylphosphino)butane) led to exclusive formation of cyclopropane 80 via decarbonylation. 

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