Uncatalyzed Diels-Alder Reaction

The hetero-Diels-Alder reaction of formaldehyde with 1,3-butadiene has been investigated with the formaldehyde oxygen atom coordinated to BH3 as a model for a Lewis acid [25 bj. Two transition states were located, one with BH3 exo, and one endo, relative to the diene. The former has the lowest energy and the calculated transition-state structure is much less symmetrical than for the uncatalyzed reaction shown in Fig. 8.12. The C-C bond length is calculated to be 0.42 A longer, while the C-0 bond length is 0.23 A shorter, compared to the uncatalyzed reac-... 

The theoretical investigations of Lewis acid-catalyzed 1,3-dipolar cycloaddition reactions are also very limited and only papers dealing with cycloaddition reactions of nitrones with alkenes have been investigated. The Influence of the Lewis acid catalyst on these reactions are very similar to what has been calculated for the carbo- and hetero-Diels-Alder reactions. The FMOs are perturbed by the coordination of the substrate to the Lewis acid giving a more favorable reaction with a lower transition-state energy. Furthermore, a more asynchronous transition-structure for the cycloaddition step, compared to the uncatalyzed reaction, has also been found for this class of reactions. 

The cycloaddition between furan and maleic anhydride was the first uncatalyzed aqueous Diels-Alder reaction reported in the literature and was studied by Diels and Alder themselves [11]. This cycloaddition was successfully revised by Woodward and Baer [12] and some years later by De Koning and coworkers [13]. The aqueous medium was also used in the cycloaddition of aromatic diazonium salts with methylsubstituted 1,3-butadienes [14]. 

The aqueous aza-Diels-Alder reaction of an aldehyde and an amine hydrochloride with a diene is catalyzed by lanthanide(III) trifluoromethane sulfonates (Ln(OTf)3, triflates [24]). Some examples are reported in Schemes 6.12 and 6.13. With respect to uncatalyzed reactions, the lanthanide catalyst allows milder reaction conditions, increases the reaction yield and does not affect the diaster-eoselectivity of the reaction, but influences the regiochemistry as in the cycloaddition of 25 with 1,3-dimethyl-1,3-butadiene (Schemes 6.10 and 6.12). These results have been applied [24b-d] to the synthesis of azasugars (Scheme 6.14). 

Engberts [3e, f, 9, 29] investigated the influence of metal ions (Co, Ni, Cu +, Zn +) on the reaction rate and diastereoselectivity of Diels-Alder reaction of dienophile 31 (Table 6.5, R = NO2) with cyclopentadiene (32) in water and organic solvents. Relative reaction rates in different media and the catalytic effect of Cu are reported in Table 6.5. 10 m Cu(N03)2 accelerates the reaction in water by 808 times, and when compared with the uncatalyzed reaction in MeCN by a factor of 232 000. 

The combination of Lewis-acid catalysis and sc-COi has also been investigated. One of these studies involved the AlCls-catalyzed Diels Alder reaction of isoprene and maleic anhydride in sc-COi at 67 °C and at 74.5-78.5 bar [89]. The reaction rate was enhanced with respect to the uncatalyzed reaction and an unconcerted two-step mechanism was suggested [89]. 

A recent report [90] investigated the Diels-Alder reaction of cyclopentadiene with various acrylates in SC-CO2 catalyzed by Sc(OTf)j. The results relative to n-butyl acrylate, in SC-CO2 and in conventional solvents, are reported in Scheme 6.34. The catalyzed reaction carried out under supercritical conditions went to completion within 15 h at 50 °C, whereas the uncatalyzed reaction proceeded only to 10 % after 24 h. An increase of endo/exo diastereoselectivity was also observed. 

There are, broadly speaking, three possible mechanisms that have been considered for the uncatalyzed Diels-Alder reaction. In mechanism a there is a cyclic six-centered transition state and no intermediate. The reaction is concerted and occurs in one step. In mechanism b, one end of the diene fastens to one end of the dienophile first to give a diradical, and then, in a second step, the other ends become fastened. A diradical formed in this manner must be a singlet that is, the... 

We first consider the simple example of an uncatalyzed Diels-Alder reaction shown in Scheme 50.2 in order to demonstrate the use of different excess experiments. The Diels-Alder reaction is known to exhibit second overall order kinetics, as shown in eq. (4). We demonstrate with this known case how reaction progress kinetic analysis may be used to extract the reaction orders in both substrate concentrations, [5] and [6]. ... 

Uncatalyzed Diels-Alder reactions between l-(trimethysiloxy)- or 1-acetoxy-l,3-butadiene and sugar-derived nitroalkenes having D-galacto or D-manno configurations proceed with complete regioselectivity. Diastereofacial selectivity is also complete with the D-galacto dieno-phile, whereas it is only moderate with the D-manno (Eq. 8.30).51... 

Desimoni and coworkers84 probed the catalytic effect of metal perchlorate salts on the rate of the Diels-Alder reactions between malonates 88 and cyclopentadiene (equation 27). They found that especially magnesium perchlorate was able to catalyze the reaction by binding two malonates in a bidentate fashion. Reaction times were shortened up to 1000 times. The endo/exo selectivity was inverted from 89/90 = 40/60 (n =4) and 17/83 (n = 5) for the thermal uncatalyzed reactions to 89/90 = 60/40 (n = 4) and 80/20 (n = 5) for the magnesium perchlorate catalyzed reactions. 

Sanders and coworkers96 97 catalyzed and directed the Diels-Alder reaction between 4-(maleimidomethyl)pyridine and 4-(3-furyl)pyridine using metalloporphyrin oligomers. When trimer 115a having three butadiyne linkers was used as the catalyst, the exo adduct was the exclusive product isolated at both 30 °C and 60 °C, whereas the uncatalyzed reaction provided an endo/exo ratio of 2/1 at 30 °C and a transient trace of endo adduct... 

Engberts and co-workers (Otto et al., 1996) reported a detailed study of a Diels-Alder reaction that was catalyzed by Lewis acids in water. They presented the results of the effects of Co Ni, Cu and Zn ions as Lewis acid catalysts on the rate and endo-exo selectivity of the DA reaction between the bidentate dienophiles 3-phenyl-l-(2-pyridyl)-2-propen-l-ones and cyclopentadiene in water (see fig. 6.6). Relative to the uncatalyzed reaction in acetonitrile, catalysis by 0.010 M Cu(N03)2 in water accelerates the Diels-Alder reaction by a factor of 79,300. Water does not induce an enhanced endo-selectivity for this reaction. 

Diels-Alder reactions.1 The diene undergoes uncatalyzed [4+2]cycloaddition with very reactive dienophiles, but generally a Lewis acid catalyst (ZnCl, or C2H5A1C12) is required. Thus, the catalyzed reaction of 1 with methyl acrylate proceeds at 0° to afford, after silyl ether cleavage, the cycloadducts 2 and 3. 

Chromium complex 53 was also shown to efficiently catalyze the inverse electron-demand hetero Diels-Alder reaction of a,(3-unsaturated aldehydes with alkyl vinyl ethers (Scheme 17.19).26 Although the uncatalyzed process required elevated temperatures and pressures to give dihydropyrans in good yields but poor endo. exo selectivities, the reaction proceeded at room temperature in the presence of 5 mol% of ent-53 and 4A molecular sieves in dichloromethane of tert-butyl methyl ether with excellent diastereoselectivity (endo. exo >96 4) and promising enantioselectivities (72-78% ee). Optimal results were achieved using a solvent-free system and excess vinyl ether. 

Pandit and co-workers adopted the same strategy to catalyze a hetero-Diels-Alder reaction in which an aryl-nitroso derivative serves as the dienophile.117 118 Antibodies generated against thebicyclic transition-state analogs 133 and 134 accelerated the reaction between the trans-diene 135 and 136, but the ratio of the two product regioisomers 137 and 138 was the same as for the uncatalyzed reaction (58 42). In experiments with stoichiometric amounts of trans-135 and antibody 309-1G7, derived from hapten 134, this ratio was altered somewhat in favor of product 138 (47 53), in accord with the structure of the... 

For the diastereoselective hetero Diels-Alder reaction of carbonyl compounds using removable chiral auxiliaries, intensive studies of the uncatalyzed... 

Another gain in diversity is achieved by the combination of these cross couplings with uncatalyzed reactions. Because of their oligounsaturated character, the coupling products are obviously well suited for subsequent peri-cyclic reactions leading to additional cyclizations. These atom-efficient processes are especially attractive since they typically proceed with high chemo-, regio- and stereoselectivity [18]. This review is intended to cover Heck reactions and related palladium-catalyzed processes followed by Diels-Alder reactions, 1,3-dipolar cycloadditions or 6 -electrocyclizations. 

Alkene- and alkyne-substituted Fischer carbenes participate as dienophiles in Diels-Alder reactions. The conditions are usually mild and the reaction proceeds smoothly at room temperature. Similar isomeric ratio and rate acceleration is observed to that of Lewis acid-promoted Diels-Alder reactions between methyl acrylates and dienes when compared to the uncatalyzed reactions. The reactions are endo-selective. Asymmetric Diels-Alder reactions are... 

The increased stereoselectivity of decatrien-3-ones relative to the n(matrien-3-ones may also be the consequence of cooperativity between twist asynchronicity and endo stabilization that both favor the c -fused product. The decatrien-3-one transitirm state is considerably less strained than the nonatrien-3-one transition state, and the uncatalyzed decatrienone cyclizations occur at or near ambient temperature. Consequently, one expects greater endo stabilization, and hence also greater cis stereoselectivity, in the decatrienone intramolecular Diels-Alder reactions. 

The readily prepared and air-stable complex trans 4, catalyzes Diels-Alder reactions between 1,3-dienes and a,]3-unsaturated methyl ketones or enals. Nitro-methane is the best solvent, and rate accelerations are up to a factor of 10 compared to the uncatalyzed reaction and up to 10 compared to catalysis by trifluoroacetic acid (Scheme 10.20) [34]. 

Bauld and coworkers, especially, developed the analogous Diels-Alder (4 + 2) cycloaddition reactions. These reactions are conveniently catalyzed by tris(4-bromophenyl)aminium hexachloroantimonate (78) or by photosensitization with aromatic nitriles. The radical cation-catalyzed Diels-Alder reaction is far faster than the uncatalyzed one, and leads to some selectivity for attack at the least substituted double bond for the monoene component (Scheme 18, 79 —> 80), but only modest endo selectivity (e- and x-80) [105]. Cross reactions with two dienes proved to be notably less sensitive to inhibition by steric hindrance of alkyl groups substituted on the double bonds than the uncatalyzed reactions, as cyclohexadiene adds detectably even to the trisubstituted double bond of 2-methylhexadiene (82), producing both 83 and 84. Dienes such as 85 react with donor-substituted olefins (86) to principally give the vinylcyclobutene products 87, but they may be thermally rearranged to the cyclohexene product 88 in good yield [105]. Schmittel and coworkers have studied the cation radical catalyzed Diels-Alder addition of both... 

The uncatalyzed Diels-Alder reaction is well known to be highly stereospecific, preferentially occurring via syn addition to both the diene and dienophilic components. Stereochemical studies of the cation radical Diels-Alder reaction have confirmed an analogous stereospecificity in two distinctly different systems. The initial study was carried out using the cycloaddition of the three geometric isomers of 2,4-hexadiene as dienophilic components and 1,3-cyclohexadiene as the diene component [39]. Each of the three isomers of the acyclic diene was found to add stereo-specifically to cyclohexadiene. In a more recent study, the cis and trans isomers of 1,2-diaryloxyethenes were found to add stereospecifically to 1,3-cyclopentadiene (Scheme 17) and also to 2,3-dimethyl-l,3-butadiene [46]. 

In so far as 4//-pyrazoles can be regarded as azadienes, the most obvious method of achieving 3,5-addition would seem to be through a Diels-Alder reaction. Unfortunately, these pyrazoles normally only react in this way with the most reactive dienophiles (4-phenyl-l,2,4-triazole-3,5-dione and cyclobutadiene ). It has recently been shown, however, that under acid catalysis a much wider range of dienophiles can be used, greatly extending the range of cyclopropyl derivatives that can be made. A typical example of an uncatalyzed reaction is that between 4,4-dimethyl-3,5-diphenyl-4i/-pyrazole and cyclobutadiene which yielded, after deazetization, 3,3-dimethyl-2,4-diphenyltricyclo[3.2.0.0 - ]hept-6-ene... 

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