1.3- Dipolar cycloaddition reactions stepwise mechanism

The most extensively studied 1,3-dipolar cycloaddition reaction so far is the prototype reaction of acetylene with fulminic acid (Scheme 1-4). The early GVB calculations by Harcourt and Little attempted to resolve the controversy between Firestone s stepwise biradical mechanism and the concerted mechanism for the 1,3-dipolar reaction [95]. Which mechanism... 

The theoretical principles of cycloaddition reactions are well understood and there have been many computational studies (see Pericyclic Reactions The Diels-Alder Reaction). Often the hetero-cycloaddition reaction shows similar characteristics to the carbocyclic analog, but a number of special features have been noted. In heterocyclic chemistry the cycloaddition reactions are often dipolar computational studies show that a concerted mechanism is followed in the gas phase. However, a number of studies have noted that these dipolar cycloaddition reactions become stepwise when solvent effects are included (via the reaction field method), with a consequent loss of stereospecificity." Other characteristics of hetero-cycloaddition reactions which have been studied include the endo/exo selectivity" and the regiose-lectivity (for example, [2-1-2] vs. [2-1-4])." High levels of electron correlation are generally required in order to establish these selectivities. 

An extensive review of the synthesis of a wide variety of five-membered heterocyclic compounds, via the formal 3-1-2-cycloaddition reactions of aziridines with alkenes, alkynes, nitriles, carbonyl groups, and heterocumulenes, has been presented." Supercritical CO2 has been used as the solvent in the formal 3-1-2-cycloaddition reactions of A-benzyl- and A-cyclohexyl-2-benzoyl-3-phenylaziridines with allenoates to yield pyrrole derivatives." The Lewis acid-catalysed intramolecular formal 3-1-2-cycloaddition reactions of 2-methyleneaziridines with tethered alkenes or alkynes (23) yielded cw-octahydrocyclopenta[c]pyrroles (24) after reductive workup. The reaction mechanism proceeds in a stepwise manner via a 2-aminoallyl cation (Scheme The Cu(I)/DTBM-Segphos-catalysed 1,3-dipolar cycloaddition reactions of a-silylimines and activated alkenes yielded highly enriched 5-unsubstituted a-quaternary proline cycloadducts with excellent diastereo- and enantio-selectivities (73-99% The... 

Such a conclusion is, nevertheless, connected with the synchronous character of the mechanism. If a stepwise process is involved (nonsimultaneous formation of the two new bonds), as for unsymmetric dienes and/or dienophiles or in hetero Diels-Alder reactions, a specific microwave effect could intervene, because charges are developed in the transition state. This could certainly be so for several cycloadditions [47, 48] and particularly for 1,3-dipolar cycloadditions [49]. Such an assumption has... 

Imino-1,2,4-thiadiazoles such as 27 react with electron-deficient alkynes to afford arylimino thiazoles such as 28. There has been some speculation as to the mechanism of this reaction, which may involve a 1,3-dipolar cycloaddition or a stepwise nucleophilic addition (Equation 6) <1996CHEC-II(4)307>. 

In accordance with theoretical predictions (90), the concerted pathway for 1,3-dipolar cycloaddition is replaced by a two-step mechanism when two requirements are satisfied. One of the criteria involves an extremely large difference in the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energies of the reaction partners. The other factor involves a pronounced steric hindrance at one termini of the 1,3-dipole (190). The first case of a stepwise... 

Amino-l,2,4-thiadiazoles 191 are obtained when ether is used (249), while 5-alkylthio-1,2,3-triazoles 192 result when the reaction is carried out in THF (250). Reaction of 3 with carbon disulfide leads to 5-alkylthio-l,2,3-thiadiazoles 193 (251). While 3 can act as a synthetic equivalent of the RC—N—N synthon (R = H, SiMea) in all these reactions, it should be emphasized that it does not react by a concerted 1,3-dipolar cycloaddition but rather by a stepwise polar mechanism. The highly nucleophilic character of 3 can account for why diazomethane and... 

The controversy between Huisgen and Firestone concerning the mechanism for 1,3-dipolar cycloaddition is longstanding.9,11 For nitrile oxide cycloadditions, experimental data have been interpreted either as supportive of a concerted mechanism9 or in favor of a stepwise mechanism with diradical intermediates.11 Theory has compounded, rather than resolved, this problem. Ab initio calculations on the reaction of fulmonitrile oxide with acetylene predict a concerted mechanism at the molecular otbital level,12,13 but a stepwise mechanism after inclusion of extensive electron correlation.14 MNDO predicts a stepwise mechanism with a diradical intermediate.13 The existence of an extended diradical intermediate such as (4 Scheme 2) has been postulated by Firestone in order to account for the occasional formation of 1,4-addition products such as the oxime (5).11 Of course, the intermediates (4) and (5) for the Firestone mechanism do not correspond to the initial transition states in Firestone s theory. These are attained prior to the formation of, and at higher energy than, the intermediates. 

Styrene and substituted styrenes react with tetramesityldisilene 1, tetra-tert-butyl-disilene 21, and tetrakis(tert-butyldimethylsilyl)disilene 22 to afford the corresponding disilacyclobutane derivatives.127,134 Similarly, [2 + 2] additions occur between the disilenes with a C = C double bond in an aromatic ring135 and acrylonitrile.136 Bains et al. have found that the reaction of disilene 1 with trans-styrene- provides a 7 3 diastereomeric mixture of [2 + 2] adducts, 201 and 202 [Eq. (95)] the ratio is changed, when czs-styrene-Ji is used.137 The formation of the two diastereomeric cyclic adducts is taken as the evidence for a stepwise mechanism via a diradical or dipolar intermediate for the addition, similar to the [2 + 2] cycloaddition of phenylacetylene to disilene ( )-3, which gives a 1 1 mixture of stereoiso-meric products.116,137... 

Both concerted and stepwise mechanisms have been proposed for these reactions although the experimental facts can be readily accounted for by the formation of a 1,4-dipolar intermediate (27 Scheme 27). The reaction rates are markedly increased in polar solvents. The cycloadditions of isocyanates to alkenes are always regiospecific, the reaction taking place so as to form the most stable 1,4-dipole. 

The past classification of the [4 + 2] cycloaddition reactions involving die 4it participation of a cationic heterodiene among the polar cycloadditions is derived not from an implied stepwise addition-cy-clization reaction mechanism but was terminology introduced to distinguish cycloadditions employing cationic or anionic components from those employing dipolar or uncharged components. Herein the reactions are simply referred to as [4 + 2] cycloaddition reactions. 

The cycloaddition between nitrones and olefins 5-9 (Scheme 2) has been thoroughly investigated.11-16 Huisgen12,13,17 formulates the reaction as a concerted 1,3-dipolar cycloaddition, but Firestone -20 formulates it as a stepwise biradical mechanism. A compromise process has been suggested 21 the accumulated evidence, however, seems to favor the concerted mechanism.22... 

The reaction of methyl 1/7-azepine-l-carboxylate with A,a-diphenylnitrone yields [2 -I- 3] dipolar cycloaddition products (28) as a mixture of exo- and e /o-isomers <92H(34)497>, the structures of which were assigned with the aid of LAOCOON III simulated NMR spectra. The almost equal distribution of isomers at C5 and the absence of any tra 5-product favors a concerted 1,3-dipolar addition rather than the involvement of a stepwise ionic mechanism, since in a stepwise reaction the conformational flexibility of the azepine ring would allow the second bond to be formed on either face of the azepine ring. 

This method is by far the most successful and most widely used in the synthesis of four-membered heterocycles with two heteroatoms. In principle these formal additions can be envisioned to occur by (a) two displacements, (b) thermal concerted [2 + 2] cycloadditions, (c) photoinduced [2 + 2] additions, (d) stepwise zwitterionic intermediates or dipolar reactants, and (e) radical intermediates. In some cases the mechanisms have been elucidated but in many others the actual mode of addition is not known. For this reason, no attempt has been made to formally divide the latter four (b-e) into categories and only the first [(a), two displacement reactions] is covered separately. 

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