Cycloaddition stepwise

Fluorinated cyclobutanes and cyclobutenes are relatively easy to prepare because of the propensity of many gem-difluoroolefins to thermally cyclodimerize and cycloadd to alkenes and alkynes. Even with dienes, fluoroolefins commonly prefer to form cyclobutane rather than six-membered-ring Diels-Alder adducts. Tetrafluoroethylene, chlorotrifluoroethylene, and l,l-dichloro-2,2-difluoroethyl-ene are especially reactive in this context. Most evidence favors a stepwise diradical or, less often, a dipolar mechanism for [2+2] cycloadditions of fluoroalkenes [S5, (5], although arguments for a symmetry-allowed, concerted [2j-t-2J process persist [87], The scope, characteristic features, and mechanistic studies of fluoroolefin... 

The reactions of bis(trifluoromethyl)-subsatuted hetero 1,3 dienes are predomi nantly LLJMO controlled processes [238] With polar or highly polarizable dieno philes, the tendency to undergo stepwise cycloaddition reactions is considerable Notably these hetero-1,3-dienes react with a,(l unsaturated hetero multiple bond systems across the hetero multiple bond exclusively [243, 246 248] (equation 53)... 

This new reaction type should be transferable to nonfluorinated hetero-1,3-di-enes that are capable of stepwise cycloaddition reactions... 

The reactions of electrophilic alkenes (alkenes attached to electron-withdrawing groups) with enamines produce one or more of the following products simple alkylation (2), 1,2 cycloaddition (3), and 1,4 cycloaddition (4). Competition with C alkylation by N alkylation is inconsequential and therefore will be largely ignored (5,7). A stepwise ionic mechanism leading to these products necessarily involves the formation of a zwitterion intermediate (1) as the first step, which is then followed either by one of the... 

There have been few mechanistic studies of Lewis acid-catalyzed cycloaddition reactions with carbonyl compounds. Danishefsky et ah, for example, concluded that the reaction of benzaldehyde 1 with trans-l-methoxy-3-(trimethylsilyloxy)-l,3-di-methyl-1,3-butadiene (Danishefsky s diene) 2 in the presence of BF3 as the catalyst proceeds via a stepwise mechanism, whereas a concerted reaction occurs when ZnCl2 or lanthanides are used as catalysts (Scheme 4.3) [7]. The evidence of a change in the diastereochemistry of the reaction is that trans-3 is the major cycloaddition product in the Bp3-catalyzed reaction, whereas cis-3 is the major product in, for example, the ZnCl2-catalyzed reaction - the latter resulting from exo addition (Scheme 4.3). 

The major developments of catalytic enantioselective cycloaddition reactions of carbonyl compounds with conjugated dienes have been presented. A variety of chiral catalysts is available for the different types of carbonyl compound. For unactivated aldehydes chiral catalysts such as BINOL-aluminum(III), BINOL-tita-nium(IV), acyloxylborane(III), and tridentate Schiff base chromium(III) complexes can catalyze highly diastereo- and enantioselective cycloaddition reactions. The mechanism of these reactions can be a stepwise pathway via a Mukaiyama aldol intermediate or a concerted mechanism. For a-dicarbonyl compounds, which can coordinate to the chiral catalyst in a bidentate fashion, the chiral BOX-copper(II)... 

Gompper et al. (1968) determined the ratio of the two final products obtained from 2-diazoniobenzenecarboxylate in the presence of furan, namely the cycloaddition product 8.31 and 2-hydroxybenzoic acid (salicylic acid). This ratio depends on the water concentration but is independent of the concentration of added furan. This observation is consistent with the stepwise formation of benzyne (route A) involving... 

The synthetic potential of such transformations for the preparation of medium-size heterocycles172 has been discussed elsewhere2. It is generally accepted that the reaction between thiirene dioxides and enamines is a stepwise (nonconcerted) thermal [2 -I- 2] cycloaddition. However, a concerted [4 + 2] cycloaddition, in which the lone pair of the enamine nitrogen atom participates, cannot be excluded. 

An analogous stepwise mechanism was also proposed by Wohrle [36] for the cation-radical-initiated cycloaddition of electron-rich allenes with pentamethyl-cyclopentadiene in the presence of tris (p-tolyl) aminium hexafluoroantimonate (TTA SbF6 ) (Equation 1.15). 

The orbital interaction depicted in Scheme 1.15 shows that the two cr-bonds form at the same time but do not develop to the same extent. The Diels-Alder cycloaddition of unsymmetrical starting materials is therefore concerted but asynchronous. A highly unsymmetrical diene and/or dienophile give rise to a highly unsymmetrical transition state and a stepwise pathway can be followed. 

Schmittel M., Woehrle C., Bohn I. Radical Cation Initiated Cycloaddition of Electron-Rich Allenes. Evidence for a Stepwise Mechanism. Acta Chem. Scand. 1997 57 151-157... 

Conjugated dienes can be dimerized or trimerized at their 1,4 positions (formally, [4 4- 4] and [4 4-4 4-4] cycloadditions) by treatment with certain complexes or other transition metal compounds. " Thus butadiene gives 1,5-cyclooctadiene and 1,5,9-cyclododecatriene. " The relative amount of each product can be controlled by use of the proper catalyst. For example, Ni P(OC6H4—o-Ph)3 gives predominant dimerization, while Ni(cyclooctadiene)2 gives mostly trimerization. The products arise, not by direct 1,4 to 1,4 attack, but by stepwise mechanisms involving metal-alkene complexes. " ... 

According to the calculations at high levels of theory, the [4+2] cycloaddition reactions of dienes with the singlet ( A oxygen follow stepwise pathways [37, 38], These results, which were unexpected from the Woodward-Hoffmann rule and the frontier orbital theory, suggest that the [4+2] cycloadditions of the singlet ( A oxygen could be the reactions in the pseudoexcitation band. 

ISOC reaction was employed to synthesize substituted tetrahydrofurans 172 fused to isoxazolines (Scheme 21) [44b]. The silyl nitronates 170 resulted via the nitro ethers 169 from base-mediated Michael addition of allyl alcohols 168 to nitro olefins 167. Cycloaddition of 170 followed by elimination of silanol provided 172. Reactions were conducted in stepwise and one-pot tandem fashion (see Table 16). A terminal olefinic Me substituent increased the rate of cycloaddition (Entry 3), while an internal olefinic Me substituent decreased it (Entry 4). 

The cycloaddition between a nitrilimine 319 and an aroyl substituted heterocyclic ketene aminal 318 has been found to be stepwise, involving an initial nucleophilic addition of 318 to 319 followed by intramolecular cyclocondensation of the intermediate 320 providing fully substituted pyrazole 321 (Eq. 36) [92]. When Ar was the 2,4-dinitrophenyl group, the intermediate 320 was isolable and required forcing conditions (xylene, reflux, 10 h) to undergo cyclization ... 

Attempts to prepare the corresponding tetrameric para-PAM from 62 were unsuccessful. Dehydrobromination in furan afforded a symanti mixture of cycloadducts 65, that were subsequently transformed to the known dibenzodiyne (66). Formation of 65 is likely to arise from stepwise elimination/cycloaddition rather than to involve the intermediacy of the highly strained tetrameric PAM. 

Such a stepwise reaction would not be expected to change the regiochemistry of cycloaddition, but it could lead to loss of stereospecificity if the zwitterionic intermediate has a long enough lifetime. In most reactions where only carbon-carbon bonds are being formed, the D-A reaction remains stereospecific. 

Lewis acid catalysis has been used to promote stepwise [2 + 2] cycloaddition of silyl enol ethers and unsaturated esters.178 The best catalyst is (C2H5)2A1C1 and polyfluoroalkyl esters give the highest stereoselectivity. The reactions give the more stable trans products. 

A theoretical study based on PM3 frontier molecular orbital (FMO) and potential energy surface (PES) analysis at the restricted Hartree-Fock (RHF)/6-31+G level was performed to examine the reaction of l-amino-2-ethoxycarbonyl-pyridinium mesitylenesulfonate and acrylonitrile in the presence of Hilnig s base leading to the formation of l,2-dihydropyrido[l,2-A]pyridazinium inner salt 17 <1999JOC9001>. The calculations indicated that both the [3+2] cycloaddition reaction and the ring expansion occurred in a concerted manner rather than through a stepwise mechanism via a zwitterionic intermediate 16 (Scheme 1). 

Cycl[3.2.2]azines may also be obtained by the cycloaddition of a bifunctional three-carbon unit to a 3//-pyrrolizine. Vinamidinium salts have been used for this purpose <1984CB1649>, although the reactions require the use of a strong base (sodium hydride) and extended reaction times. They appear to proceed via a stepwise mechanism, since intermediates (the conjugated enamines 354 and 355) have been isolated in certain cases (Scheme 94). 

Concerted [3 + 2] cycloaddition was proposed as the mechanism for dihydroxylation originally by Boesken195 and Criegee166 and reiterated in a refined manner by Corey.172 196 197 Another mechanism, stepwise [2 + 2] cycloaddition, has been proposed by Sharpless (Scheme 50).198-200... 

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