CONIA Cyclization

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). 

The Conia-ene reaction is a thermal cyclization of an alkyl ketone with an alkyne to give the corresponding a-vinylated ketone.98 The catalytic version of this reaction has been reported to generalize the process to more functionalized substrates.99 The intramolecular carbocupration of alkyne 94 has been investigated under basic conditions in the presence of a catalytic amount of copper iodide (Scheme 28).100 The cyclic product 95 is obtained in high yield. 

Allenyl ketones can undergo a Conia-ene cyclization, as shown in Eq. 13.56 [65]. Heating ketone 166 at 275 °C for 15 min leads to acetylcyclopentene 168 in 70% yield. Cyclization presumably takes place through a pericyclic mechanism involving enol 221. 

The phyllocladane skeleton 131 was constructed efficiently by stereoselective formations of six carbon-carbon bonds and four rings via a one-pot sequence of cyclizations the ene type, [2+2+2], and [4+2] cycloadditions. In this synthesis, the Conia ene reaction of 127 takes place under mild conditions to generate 128, and the cyclotrimerization of its diyne with 118 gives 129. These two reactions are catalysed by CpCo(CO)2. Finally, ring-opening to give 130 and intramolecular Diels-Alder reaction in the presence of DPPE produced the phyllocladane skeleton 131 in a total yield of 42% [55]. 

The Conia-ene reaction was brought to the held of gold catalysis by Toste et al.29 It provided very mild conditions for this cyclization to a functionalized hve-membered ring (Scheme 12.14). 

The thermal cyclization of ketones onto alkynes, the Conia-ene reaction, can proceed thermally but only at inconveniently high temperatures.39 Transition metals can catalyse it at lower temperatures but they require enolate generation, strong acid or photochemical activation. In the presence of phosphaneAu1 complexes, however, the reaction proceeds at ambient temperature under neutral conditions. For example, the following ketoester was converted into the cyclic product in 94% yield in 15 min in the... 

Rotane was first synthesized by Rippol and Conia. The key steps included the synthesis of dispirononanone 13 (equation 11). Condensation of 13 with formaldehyde provided the tetrahydroxymethyl derivative 32, which was converted into the tetraspiro compound 33 by tosylation-bromination followed by reductive cyclization. Subsequent Wittig methylenation and cyclopropanation of the ketone 33 completed the synthesis (equation 30). 

A major advance in the past decade has been the development of catalysts for the cyclization of al-kynic ketones. Jackson and Ley found that (192) cyclizes to (193) in quantitative yield on heating at 280 °C, treatment with Znh in toluene at reflux or treatment with SnCU in CH2CI2 at 25 "C. ° Conia has found that double catalysis by H" and Hg + lowers the temperature necessary to achieve cyclization. Treatment of (178) with hydrochloric acid and mercury(II) chloride in 1,1,2,2-tetrachloroethane at 110 °C gives the isomer of (179) with one endocyclic double bond in 43% yield and the monocyclized product in 23% yield. Improved results were obtained with Hg + on a solid support. ... 

Drouin, Conia et al. have found that these reactions can be carried out under even milder conditions by cyclization of silyl enol ethers of alkynones. Treatment of (194), as an (E)-(Z) mixture, with HgCb in CH2CI2 in the presence of hexamethyldisilazene for 30 min at 30 C gives vinylmercurial (195 R = HgCl) in quantitative yield. Cleavage of the carbon-mercury bond can be carried out to give (195 R - H, D, CQzMe, Br or COMe). 

Minato et have reported the isolation of acorenone (149) from Acorus calamus L. The physical properties (m.p., [ajp) which they ascribe to this compound are markedly different from two previous sets of data. Hydrogenation ofacorenone is reported to give isoacorone (150 R = Me, = H)andacorone (150 R = H, R = Me). Recently, Conia et al. have demonstrated that thermal cyclization (220 °C) of the appropriately substituted cyclohexanone (151) [derived from (-+- )-3-methylcyclohexanone] yielded four isomeric spiro-diketones closely related to the acorane skeleton. The intermediacy of the isopropylidene isomer (152) was indicated and from a detailed study of n.m.r. solvent shifts and c.d. spectra it was concluded that these four spiro-diketones can be represented as (153)—(156). 

CycHzation of N-ailylamides to e-iactams, Conia et a/. have reported cyclization of N-allylamides of type I to e-lactams 2 and 3. Certain conditions are mandatory for this cyclization. can be H or an alkyl group R and R cannot be hydrogen. The nitrogen atom cannot be trisubstituted. A slight excess of base is required and no cyclization is observed when NaH is replaced by LiH, KH, or NaNHa. 

The intramolecular ene reaction with an enol as the ene component is known as the Conia reaction. Very high temperatures are normally required and more efficient is the use of a cobalt catalyst or the use of a zinc enolate. Thus, formation of the zinc enolate 257 from the ester 256 promoted cyclization at room temperature to give, after quenching the intermediate organozinc species with a proton, the cis pyrrolidine 258 (3.164). 

The possibility of developing activated ene donors is discussed above. As active donors are coupled with active acceptors, it may be possible to develop routes to heretofore relatively inaccessible ring systems and substitution patterns. In particular, one or more of the interacting carbon atoms could be replaced with a heteroatom. Several such systems, as exemplified by the acyl nitroso acceptors of Keck [26], the Lewis acid-mediated carbonyl acceptors developed by Snider [27], and the enol donor cyclizations of Conia [28], have already been investigated. 

Ene Reactions.—Conia, who has done so much to demonstrate the synthetic utility and versatility of unsaturated carbonyl compound cyclizations, as exemplified by the prototype conversion of(271) into (272), has reviewed recent developments which includes applications to bridged-ring compound synthesis. The same group have reported on the double thermal cyclization of 3,3-dibutynylcyclopentanone (273) to give the [3,3,3]propellenes (274 60%) and (275 5%), and the monocyclization product (276 10%). Since (274) is stable under the reaction conditions, (275) is presumably formed from (276) by isomerization prior to a second ene cyclization step. 

A combination of experimental results and quantum mechanical calculations has contributed to the understanding of the enantioselective Conia-ene cyclization of alkyne-tethered / -ketoesters (144), catalysed by the cinchona-derived urea pre-catalysts (146) and TfOCu, which affords (145) with <93%... 

Two types of carbon nucleophiles are commonly utilized in gold catalysis electron-rich (hetero)arenes [3,6] and 1,3-carbonyl compounds [94—104]. The first will be discussed later. The addition of 1,3-carbonyl compounds to alkynes, known as the Conia-ene cyclization [94—104], takes place via the corresponding enol tautomer or the corresponding silyl enol ether (Scheme 1.4). 

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