Zwitterion intermediate

To synthesize the monoxacetam stmctures (Fig. 6), alkylation of A/-protected 1-hydroxyazetidinones (46) with the appropriate haloacetic acid derivatives provided (47). Alternatively, (47) could be prepared from the acycHc hydroxamate ester (48). Deprotection of (47) furnished the zwitterionic intermediate (49) [90849-16-4] CgH2QN204, which subsequendy underwent acylation using the C-3 aminothiazole oxime side chain to afford SQ 82,291 (45) also known as oximonam (37). 

The rearrangement (automerization) of Dewar thiophene 5-oxide (61), observed by NMR, occurs so much more rapidly than that of the corresponding episulfide that special mechanisms have been invoked. The one which involves a zwitterionic intermediate (Scheme 108) is favored over a pseudopericyclic sulfur-walk mechanism in which the electrons of the carbon-sulfur o--bond and the pair of electrons on sulfur exchange places as the sulfur atom migrates around the ring (80JA2861). 

The predominant, if not exclusive, formation of 5/7-fused hydroxy ketones was observed in the case of 4-alkylated dienones [(204) (205) (R = CH3) 6 1 from (201) (R = CH3)] ° and of prednisone 21-acetate [(206)-> (207)]. It appears therefore likely that intermediates which represent the conjugate acids of the postulated zwitterionic intermediates in the dienone photoisomerizations [c/. (202), (203)] participate both in the acid-catalyzed transformations of (200) and in the dienone photochemistry in protic solvents. 

Both terminal and nonterminal acetylenes have been used. Activating groups oL to the acetylenic bond have included sulfone (131-135), sulfoxide (134), ester (28,133-139), and ketone (134,140). Whether adduct 183 Is designated as cis or trans depends on the investigators and the particular compound. If the addition reaction is carried out in aprotic solvents, the major isomer is 183 formed by cis addition (135,138,139). For example, the addition of aziridine to dimethyl acetylenedicarboxylate (182, X, Y = CO2CH3) in dimethyl sulfoxide (135) gave 75 % of a mixture containing 95 % of the Chester 185. Collapse of the intermediate zwitterion intermediate 186... 

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... 

Olefins conjugated with electron-withdrawing groups other than a carbonyl group undergo reactions with enamines in a manner similar to the carbonyl-conjugated electrophilic alkenes described above. Namely, they condense with an enamine to form a zwitterion intermediate from which either 1,2 cycloaddition to form a cyclobutane ring or simple alkylation can take place. 

The initial reaction between a ketene and an enamine is apparently a 1,2 cycloaddition to form an aminocyclobutanone adduct (58) (68-76a). This reaction probably occurs by way of an ionic zwitterion intermediate (75). The thermal stability of this adduct depends upon the nature of substituents Rj, R2, R3, and R. The enolic forms of 58 can exist only if Rj and/or R4 are hydrogens. If the enamine involved in the reaction is an aldehydic enamine with no 3 hydrogens and the ketene involved is di-substituted (i.e., R, R2, R3, and R4 are not hydrogens), then the cyclo-butanone adduct is thermally stable. For example, the reaction of dimethyl-ketene (61) with N,N-dimethylaminoisobutene (10) in isopropyl acetate... 

Thus the reactions of cyclic or acyclic enamines with acrylic esters or acrylonitrile can be directed to the exclusive formation of monoalkylated ketones (3,294-301). The corresponding enolate anion alkylations lead preferentially to di- or higher-alkylation products. However, by proper choice of reaction conditions, enamines can also be used for the preferential formation of higher alkylation products, if these are desired. Such reactions are valuable in the a substitution of aldehydes, which undergo self-condensation in base-catalyzed reactions (117,118). Monoalkylation products are favored in nonhydroxylic solvents such as benzene or dioxane, whereas dialkylation products can be obtained in hydroxylic solvents such as methanol. The difference in products can be ascribed to the differing fates of an initially formed zwitterionic intermediate. Collapse to a cyclobutane takes place in a nonprotonic solvent, whereas protonation on the newly introduced substitutent and deprotonation of the imonium salt, in alcohol, leads to a new enamine available for further substitution. 

Unsaturated sulfoncs (314,315) and nitroolcfins (303,315-317) also give alkylation products with enamines. In the latter reactions the formation of nitroethyl or cyclobutane derivatives has been found (316) to depend on the reaction medium as well as steric and electronic parameters which determine the fate of zwitterionic intermediates. Thus no enamine products could... 

In the reactions of benzyne with enamines, arylated enamines or amino-benzocyclobutenes can be obtained, depending on reaction conditions and the structure of the enamine. Thus the presence of a proton source such as a secondary amine will favor the enamine product through capture of the zwitterionic intermediate, whereas in the absence of protons one sees... 

The presence of an substituent, found in the pyrrolidine enamine of 2-methylcyclohexanone, blocks the possibility of an intramolecular proton transfer in the zwitterionic intermediate and thus only the benzocyclobutane... 

Conjugated dienamines were found to give predominantly double four-membered-ring adducts as well as a small amount of the six-membered-ring adduct (466,468). This important result indicates preferred attack at the terminal carbon of the dienamine system (in contrast to alkylation, for instance) in the generation of an initial zwitterionic intermediate. Addition of sulfonyl chloride and triethylamine to a homocyclic dienamine gave only the bridged product (446). 

Reactions of vinylogous amides with methanesulfonyl chloride also led to the formation of six-membered rings. Here the initial attack on oxygen produces a zwitterionic intermediate which can collapse to an enol sulfonic acid lactone (383,469). 

The reactions of enamines as 1,3-dipolarophiles provide the most extensive examples of applications to heterocyclic syntheses. Thus the addition of aryl azides to a large number of cyclic (596-598) and acyclic (599-602) enamines has led to aminotriazolines which could be converted to triazoles with acid. Particular attention has been given to the direction of azide addition (601,603). While the observed products suggest a transition state in which the development of charges gives greater directional control than steric factors, kinetic data and solvent effects (604-606) speak against zwitterionic intermediates and support the usual 1,3-dipolar addition mechanism. 

Theoretical calculations explain the photochemical behavior of phenylthiazoles (Fig. 14) (99MI233). The RCRE mechanism cannot be invoked because the radical intermediates have higher energies than the corresponding triplet states. Furthermore, the formation of the Dewar isomer is favored in comparison with the formation of the zwitterionic intermediate. Nevertheless, the reaction conditions used by Kojima and Maeda could allow for an endothermic reaction giving this type of intermediate. The same results were obtained using 2,5-diphenylthiazole. 

The reaction starts with the nucleophilic addition of a tertiary amine 4 to the alkene 2 bearing an electron-withdrawing group. The zwitterionic intermediate 5 thus formed, has an activated carbon center a to the carbonyl group, as represented by the resonance structure 5a. The activated a-carbon acts as a nucleophilic center in a reaction with the electrophilic carbonyl carbon of the aldehyde or ketone 1 ... 

Together with a shift of the proton from the a-carbon to the alkoxide oxygen, the tertiary amine is eliminated from the addition product to yield the unsaturated product 3. Early examples of the Baylis-Hillman reaction posed the problem of low conversions and slow reaction kinetics, which could not be improved with the use of simple tertiary amines. The search for catalytically active substances led to more properly adjusted, often highly specific compounds, with shorter reaction times." Suitable catalysts are, for example, the nucleophilic, sterically less hindered bases diazabicyclo[2.2.2]octane (DABCO) 6, quinuclidin-3-one 7 and quinuclidin-3-ol (3-QDL) 8. The latter compound can stabilize the zwitterionic intermediate through hydrogen bonding. ... 

Snider and coworkers125 have reported the Lewis acid catalyzed [2 + 2]cycloaddition of (phenylsulfonyl)allene 112. The reaction with methylenecyclohexane in dichloro-methane gives a 25% yield of an 8 1 mixture of 210 and 211 (equation 132). An addition reaction of l-(p-tolylsulfonyl)ethylene with enamines gives aminocyanobutanes via the zwitterionic intermediate (212) as shown in equation 133126. 

Scheme 13 Possible mode of formation of the cyclopentadiene 61 isomeric with 60a by 1,2-migration of the dimethylamino group via a bridged zwitterionic intermediate 62 [44]...

Stabilised sulphur ylides react with alkenylcarbene complexes to form a mixture of different products depending on the reaction conditions. However, at -40 °C the reaction results in the formation of almost equimolecular amounts of vinyl ethers and diastereomeric cyclopropane derivatives. These cyclopropane products are derived from a formal [2C+1S] cycloaddition reaction and the mechanism that explains its formation implies an initial 1,4-addition to form a zwitterionic intermediate followed by cyclisation. Oxidation of the formed complex renders the final products [30] (Scheme 8). 

Non-enolizable imines such as 9-fluorene imines react with alkynylcarbene complexes to afford mixtures of mesoionic pyrrolium carbonyltungstates and dihydropyrrole derivatives [68] (Scheme 23). Although both compounds can be considered as [3C+2S] cycloadducts, formation of each of them follows a very different pathway. However, the first intermediate of the reaction is common for both compounds and supposes the conjugated addition of the imine to the alkynylcarbene complex to form a zwitterionic intermediate. A cyclisation... 

The mechanism for aldehyde-derived enamines involves a Michael-type 1,4-addition of the enamine to the alkenylcarbene complex to generate a zwit-terionic intermediate which evolves to the final product by cyclisation. On the other hand, ketone-derived enamines react through an initial 1,2-addition to the carbene carbon to generate a different zwitterionic intermediate. Then, a [l,2]-W(CO)5 shift-promoted ring closure produces a new intermediate which, after elimination of the metal moiety, furnishes the corresponding cyclopen-tene derivatives (Scheme 30). 

The a-substitution in the alkenylcarbene complex seems to be crucial to direct the reaction to the five-membered rings. The mechanism proposed for this transformation supposes an initial 1,2-addition of the enolate to the carbene carbon atom to generate a zwitterionic intermediate. Cyclisation promoted by... 

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