Stepwise Diels-Alder reactions

In a recent experimental study of the femtosecond dynamics of a Diels-Alder reaction in the gas phase it has been suggested that both concerted and stepwise trajectories are present simultaneously It is interesting to read the heated debates between Houk and Dewar on the... 

Conjugated cations, anions and radicals can give the Diels-Alder reaction. In such a case, the two cr bonds are formed in two separate steps (stepwise... 

As a continuation of these studies, Bauld recently reported evidence of a stepwise mechanism in the cation-radical Diels-Alder reaction of phenyl vinyl sulfide with cyclopentadiene [34, 35] (Scheme 1.6). 

Processes consisting of two or more synthetic steps carried out in the same flask without isolating any intermediates have been widely investigated in the last decade due to their ecological and economic advantages when compared to a stepwise procedure. In this respect the Diels-Alder reaction is a frequent example. 

Starting from 27, cyclo-Cig was prepared in the gas phase by laser flash heating and the neutral product, formed by stepwise elimination of three anthracene molecules in retro-Diels-Alder reactions, was detected by resonant two-photon-ionization time-of-flight mass spectrometry [23]. However, all attempts to prepare macroscopic quantities of the cyclocarbon by flash vacuum pyrolysis using solvent-assisted sublimation [50] only afforded anthracene and polymeric material. 

The spiro dimer of a-tocopherol (9, see also Fig. 6.4) is formed as mixture of two diastereomers by dimerization of the o-QM 3 in a hetero-Diels-Alder reaction with inverse electron demand. Both isomers are linked by a fluxion process (Fig. 6.22), which was proven by NMR spectroscopy.53 The detailed mechanism of the interconversion, which is catalyzed by acids, was proposed to be either stepwise or concerted.53-55... 

Chen, J., Houk, K. N., Foote, C. S., 1998, Theoretical Study of the Concerted and Stepwise Mechanisms of Triazolinedione Diels-Alder Reactions , J. Am. Chem. Soc., 120, 12303. 

Thus BCP seems to follow two competitive pathways in the cycloaddition with dienes (i) a stepwise diradical process giving the [2 + 2] adduct, or (ii) a concerted pathway giving the [4 + 2] adduct. Accordingly, the proportion of the latter increases with the reactivity of diene in Diels-Alder reactions. Conversely, the reaction with 2,3-dicyanobutadiene (529), generated in situ by electrocyclic ring-opening of 1,2-dicyanoeyelobutene [142], furnishes selectively the [2 + 2] cycloadduct 530 (Table 42, entry 4) due to the presence of substituents able to stabilize the diradical intermediate [13b],... 

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... 

The observation that the transition state volumes in many Diels-Alder reactions are product-like, has been regarded as an indication of a concerted mechanism. In order to test this hypothesis and to gain further insight into the often more complex mechanism of Diels-Alder reactions, the effect of pressure on competing [4 + 2] and [2 + 2] or [4 + 4] cycloadditions has been investigated. In competitive reactions the difference between the activation volumes, and hence the transition state volumes, is derived directly from the pressure dependence of the product ratio, [4 + 2]/[2 + 2]p = [4 + 2]/[2 + 2]p=i exp —< AF (p — 1)/RT. All [2 + 2] or [4 + 4] cycloadditions listed in Tables 3 and 4 doubtlessly occur in two steps via diradical intermediates and can therefore be used as internal standards of activation volumes expected for stepwise processes. Thus, a relatively simple measurement of the pressure dependence of the product ratio can give important information about the mechanism of Diels-Alder reactions. 

SCHEME 3. Comparison of van der Waals volumes of reaction and activation with the volumes of reaction and activation calculated for a pericyclic and stepwise Diels-Alder reaction of 1,3-butadiene with ethene... 

These experimental secondary deuterium KIEs observed in Diels-Alder reactions have been compared with the respective theoretical KIEs for the stepwise mechanism involving a diradical intermediate (equation 88a) and for concerted synchronous and asynchronous mechanisms (equation 88b) for the Diels-Alder reaction of butadiene with ethylene207. 

Mechanistic and theoretical studies of the Diels-Alder reaction have resulted in the characterization of this reaction as a concerted, although not necessarily synchronous, single-step process28-31 45. The parent reaction, the addition of 1,3-butadiene to ethylene yielding cyclohexene, has been the subject of an ongoing mechanistic debate. Experimental results supported a concerted mechanism, whereas results from calculations seemed to be dependent on the method used. Semi-empirical calculations predicted a stepwise mechanism, whereas ab initio calculations were in favor of a concerted pathway. At the end of the 80s experimental and theoretical evidence converged on the synchronous mechanism29-31. 

The Diels-Alder reaction is the best known and most widely used pericyclic reaction. Two limiting mechanisms are possible (see Fig. 10.11) and have been vigorously debated. In the first, the addition takes place in concerted fashion with two equivalent new bonds forming in the transition state (bottom center, Fig. 10.11), while for the second reaction path the addition occurs stepwise (top row, Fig. 10.11). The stepwise path involves the formation of a single bond between the diene (butadiene in our example) and the dienophile (ethylene) and (most likely) a diradical intermediate, although zwitterion structures have also been proposed. In the last step, ring closure results with the formation of a second new carbon carbon bond. Either step may be rate determining. 

Fig. 10.11 The stepwise and concerted mechanisms for the Diels-Alder reaction between butadiene and ethylene. The reactants (lower left) proceed to the product, cyclohexene (lower right) either through a two step, two transition state mechanism involving the formation of a diradical intermediate (top center), or more directly through the symmetric synchronous transition state (bottom center) (Storer, J. W., Raimondi, L., and Houk, K. N., J. Am. Chem. Soc. 116, 9675 (1994))...

Stepwise TS of the Diels-Alder Reaction CASSCF/3-21G (CASSCF/6-31 G")... 

Fig. 10.12 (a) Transition state structures (C—C bond lengths) calculated at two levels for the concerted and step-wise Diels-Alder reaction shown in Fig. 10.11 (Houk, K. N., Gonzalez, J., and Li, Y,Accts. Chem. Res. 28, 81 (1995). The parenthesized values show results for calculations at a much higher (and much more expensive) level, (b) Calculated secondary deuterium isotope effects, kH/kD (per D) for the concerted and stepwise Diels-Alder reactions shown in Fig. 10.11 (Houk, K. N., Gonzalez, J., and Li, Y,Accts. Chem. Res. 28, 81 (1995). The parenthesized values show results for calculations at a much higher (and much more expensive) level)...

A semiempirical AMI study of the inverse-electron-demand Diels-Alder reaction of 4-substituted 6-nitrobenzofurans with enol ethers and enamines favours a stepwise mechanism involving short-lived diradical intermediates. The inverse-electron-demand intermolecular Diels-Alder reactions of 3,6-bis(trifluoromethyl)-l,2,4,5-tetra-zine with acyclic and cyclic dienophiles followed by the elimination of N2 produce 4,5-dihydropyridazines, which cycloadd further to yield cage compounds. The preparation of jS-carbolines (90) via an intramolecular inverse-electron-demand Diels-Alder... 

Methyl 2-bromo-2-cyclopropylideneacetate (11a) has never been tested in these reactions, but has been used as a starting material for the stepwise construction of 1,6-heptadienes with methylenecyclopropane units for intramolecular Heck reactions. Thus, bromo ester 11a, after reduction, subsequent conversion of the resulting alcohol to the bromide and coupling with enolates of substituted malonates, was transformed into dienes of the type 254 (Scheme 73) - versatile synthetic blocks for the preparation of functionally substituted spirocyclopropanated bicyclo[4.3.0]nonenes 255a-d by a domino Heck-Diels-Alder reaction [122a]. 

An intramolecular hetero-Diels-Alder reaction has been used to prepare octahydro-14//-benzo[g]quinolino[2,3- 7]-quinolidines (Scheme 38) <1998BML2881>. The same researchers have published a major study on the mechanism of this hetero-Diels-Alder reaction and have shown that under Lewis acid-catalyzed conditions it proceeds via a stepwise mechanism <1996T955>. 

Intramolecular ionic Diels-Alder reactions were carried out in highly polar media to afford carbocyclic ring systems. The strategy, which obviates the need for high temperatures and pressures, features in situ generation of heteroatom-stabUized allyl cations that undergo subsequent (4 + 2) cycloaddition at ambient temperature. Typically, reactions were complete within 1 hour after addition of substrate. Some cycloadducts were the result of a concerted process, whereas others were formed via a stepwise reaction mechanism (Grieco, 1996). 

Olefins can add to double bonds in a reaction different from those discussed in 5-15, which, however, is still formally the addition of RH to a double bond. This reaction is called the ene synthesis44,1 and bears a certain similarity to the Diels-Alder reaction (5-47). For the reaction to proceed without a catalyst, one of the components must be a reactive dienophile (see 5-47 for a definition of this word) such as maleic anhydride, but the other (which supplies the hydrogen) may be a simple alkene such as propene. There has been much discussion of the mechanism of this reaction, and both concerted pericyclic (as shown above) and stepwise mechanisms have been suggested. The reaction between maleic anhydride and optically active PhCHMeCH=CH2 gave an optically active product,441 which is strong evi-... 

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