Diels-Alder reactions with inverse electron demand

Bis(trifluoromethyl)-substituted heterodienes are electron-deficient species They therefore react preferentially with electron-rich multiple bond systems to give [4+2] cycloadducts (Diels-Alder reaction with inverse electron demand) [238]... 

Honk et al. concluded that this FMO model imply increased asynchronicity in the bond-making processes, and if first-order effects (electrostatic interactions) were also considered, a two-step mechanisms, with cationic intermediates become possible in some cases. It was stated that the model proposed here shows that the phenomena generally observed on catalysis can be explained by the concerted mechanism, and allows predictions of the effect of Lewis acid on the rates, regioselectivity, and stereoselectivity of all concerted cycloadditions, including those of ketenes, 1,3-dipoles, and Diels-Alder reactions with inverse electron-demand [2],... 

The two transition states in Figs 8.5 and 8.6 correspond in principle to a metal-catalyzed carho-Diels-Alder reaction under normal electron-demand reaction conditions and a hetero-Diels-Alder reaction with inverse electron-demand of an en-one with an alkene. The calculations by Houk et al. [6] indicated that with the basis set used there were no significant difference in the reaction course. 

There are Diels-Alder reactions known where the electronic conditions outlined above are just reversed. Such reactions are called Diels-Alder reactions with inverse electron demand For example the electron-poor diene hexachlorocy-clopentadiene 21 reacts with the electron-rich styrene 22 ... 

However, when 3,5-diphenyl-4//-pyrazol-4-one, a reagent that undergoes Diels- Alder reactions with inverse-electron demand, is used, addition of the 2,4-diene part of oxepin to one of the two C-N double bonds of the pyrazolone is observed to give 4.232... 

An interesting combination of enzymatic with non-enzymatic transformation in a one-pot three-step multiple sequence was reported by Waldmann and coworkers [82]. Phenols 125 in the presence of oxygen and enzyme tyrosinase are hydroxylated to catechols 126 which are then oxidized in situ to ortho quinones 127. These intermediates subsequently undergo a Diels-Alder reaction with inverse electron demand by reaction with different dienophiles (Table 4.19) to give endo bicyclic 1,2-diketones 128 and 129 in good yields. 

The domino reaction consists of a Knoevenagel condensation giving an intermediate which immediately undergoes an intramolecular hetero-Diels-Alder reaction with inverse electron demand [18]. 

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... 

A further hetero-Diels-Alder reaction with inverse electron demand between o-QM 3 as the dienophile and either of the two diastereomers of spiro dimer 9 as the diene provided the spiro trimers 31 and 32 (Fig. 6.25). The absolute configuration was derived from NMR experiments. It was moreover shown that only two of the four possible stereoisomeric trimers were formed in the hetero-Diels-Alder reaction the attack of the o-QM 3 occurred only from the side syn to the spiro ring oxygen.28... 

In the Diels-Alder reaction with inverse electron demand, the overlap of the LUMO of the 1-oxa-l,3-butadiene with the HOMO of the dienophile is dominant. Since the electron-withdrawing group at the oxabutadiene at the 3-position lowers its LUMO dramatically, the cycloaddition as well as the condensation usually take place at room or slightly elevated temperature. There is actually no restriction for the aldehydes. Thus, aromatic, heteroaromatic, saturated aliphatic and unsaturated aliphatic aldehydes may be used. For example, a-oxocarbocylic esters or 1,2-dike-tones for instance have been employed as ketones. Furthermore, 1,3-dicarbonyl compounds cyclic and acyclic substances such as Meldmm s acid, barbituric acid and derivates, coumarins, any type of cycloalkane-1,3-dione, (1-ketoesters, and 1,3-diones as well as their phosphorus, nitrogen and sulfur analogues, can also be ap-... 

Cycloadditions of reactants with opposite electronic properties are defined as Diels-Alder reactions with inverse electron demand or inverse Diels-Alder reactions. 

In addition to the reaction of vinylcarbene complexes with alkynes, further synthetic procedures have been developed in which Fischer-type carbene complexes are used for the preparation of benzenes. Most of these transformations are likely to be mechanistically related to the Dbtz benzannulation reaction, and can be rationalized as sequences of alkyne-insertions, CO-insertions, and electrocycli-zations. A selection of examples is given in Table 2.18. Entry 4 in Table 2.18 is an example of the Diels-Alder reaction (with inverse electron demand) of an enamine with a pyran-2-ylidene complex (see also Section 2.2.7 and Figure 2.36). In this example the adduct initially formed eliminates both chromium hexacarbonyl ([4 -I- 2] cycloreversion) and pyrrolidine to yield a substituted benzene. 

The classical 4 + 2 Diels-Alder reaction involves the thermally allowed cycloaddition of an electron-rich (nucleophilic) diene a=b-c=d with an electron-deficient (electrophilic) dienophile e=f. In the polar cycloaddition reactions considered here, the a=b-c=d system bears a positive charge and is so obviously ill-suited for a nucleophilic role that the first examples of polar cycloaddition appeared inexplicable in terms of cycloaddition theory then current. In 1962 Sauer and Wiest demonstrated the existence of a Diels-Alder reaction with inverse electron demand in which the electronic roles of a=b-c=d and e=f are exchanged, with the former becoming the electrophile and the latter... 

Aiming at the pyranose form of sugars, normal type hetero-Diels-Alder reactions were extensively used for the synthesis of functionally substituted dihydropyran and tetrahydropyran systems (5-10) (see routes A - D in the general Scheme 1) which are also important targets in the "Chiron approach" to natural product syntheses (2.) Hetero-Diels-Alder reactions with inverse electron demand such as a, p-unsaturated carbonyl compounds (l-oxa-1,3-dienes) as heterodienes and enol ethers as hetero-dienophiles, are an attractive route for the synthesis of 3,4-dihydro-2H-pyrans (11). 

Despite the concerted nature of most Diels-Alder reactions, substituent effects are evident. Electronic compatibility of the reaction partners is of paramount importance, therefore while a normal Diels-Alder reaction is characterized by the union of an electron-rich diene and an electron-poor dienophile, the Diels-Alder reaction with inverse electron demand features an electron-poor diene and electron-rich dienophile. 

Because of the strong rr-deficiency of most six-membered heteroaromatic compounds, cycloadditions of this type belong to Diels-Alder reactions with inverse electron demands in other words, they are LUMO -HOMOp, controlled reactions (for review see (B-87MI 502-08)). Acceptor substituents in the heterocyclic diene and donor substituents in the dienophile accelerate the reaction, as shown by kinetic data (83TL1481,84TL2541,90TL6851). 

Finally, a Diels-Alder reaction with inverse electron demand, in which the thiophene acts as the 27r-component, has been reported (78AP728). Tetrazinedicarboxylic ester adds to thiophenes to give the adduct (290) loss of nitrogen from this is followed by oxidation, yielding the thieno[2,3-rf]pyridazines (291) in 10-15% yield. With 2,5-dimethyl-thiophene as the substrate, aromatization is blocked, and the product (292) is obtained in 57% yield. 

Triazines are reactive electron-deficient dienes in Diels-Alder reactions with inverse electron demand. They react with alkenes, strained double bonds, electron-rich and electron-deficient alkynes and C=N double bonds. In most cases it is found that the dienophile addition occurs across the 3- and 6-positions of the triazine ring, but ynamines can also add across the 2- and 5-positions. The reactions are still under active theoretical and practical investigation. 

Tetrazines (624) are reactive dienes in Diels-Alder reactions with inverse electron demand. They react with both C—C and C—N multiple bonds. Cycloaddition of (624) with imidates thus affords 1,2,4-triazines (625) which are formed via the bicyclic intermediates (626) and the dihydro-1,2,4-triazines (627) (69JHC497). Further studies have been made on the limitations of this reaction. 

In the presence of aluminum chloride, which presumably lowers the energy of the LUMO of the heterodiene by Lewis acid complexation, electron-rich alkenes give dihydropyrans on reaction with acyl cyanides at room temperature (82AG(E)859). Unsaturated esters further extend the range of diene components of value in these Diels-Alder reactions with inverse electron demand (82TL603). 

The endo rule also applies to some Diels-Alder reactions with inverse electron demand, as in the cycloaddition of butadienylsulfoxide 2.116 with the enamine 2.117, which gives only the adduct 2.118. The amino group is an... 

A Diels-Alder reaction with inverse electron demand... 

Most of the examples in this chapter so far probably do not have this feature, with the possible exception of the Diels-Alder reaction with inverse electron demand 2.117 —> 2.118, and are therefore likely to be pericyclic... 

Dienes and dienophiles should have complementary electronic character. In the majority of reported examples the diene bears electron-donating substituents, and the dienophile electron-attracting substituents. In a small number of reactions, known as Diels-Alder reactions with inverse electron demand, an electron-deficient diene reacts with an electron-rich dienophile. The first group of reactions has been studied thoroughly with important modifications that affect the complementary electronic character of the diene and dienophile or the steric requirements. 

Diels-Alder Reactions with Inverse Electron Demand... 

Diels-Alder reactions also may occur when the electronic situation of the substrates is completely reversed, that is, when electron-rich dienophiles react with electron-poor dienes. [4+2]-Cycloadditions of this type are called Diels-Alder reactions with inverse electron demand. 1,3-Dienes that contain heteroatoms such as O and N in the diene backbone are the... 

Fig. 15.23. Diels-Alder reactions with inverse electron demand reactivity increase by the use of donor-substituted dienophiles (X refers to a substituent that may be a donor or an acceptor).

The most important stabilizing interaction of the transition states of Diels-Alder reactions with inverse electron demand is due to the second term of Equation 15.3. In this case, the denominator of the second term is substantially smaller than that of the first term. This is because the HOMO of an electron-rich dienophile is closer to the LUMO of an electron-poor diene than is the HOMO of the same diene relative to the LUMO of the same dienophile (Figure 15.24, column 4). We saw the reason for this previously acceptors lower the energies of all 7F-type MOs donors increase these energies. 

The domino reaction consists of a Knoevenagel condensation giving an intermediate that immediately undergoes an intramolecular hetero-Diels-Alder reaction with inverse electron demand [31]. As aldehydes, rac-dtronellal, an aromatic aldehyde, and two commercially available 1,3-diketones, 1,3-dimethylbarbituric add and Meldrum s acid, were seleded. By combinations of these reactants, different cycloadducts were generated. 

Due to their two electron-withdrawing groups, / ,/ -diketoenamines are reactive towards nucleophilic reagents. Attack usually occurs at the a-carbon. With dinucleophiles, the substitution of the amino group is followed by ring closure to 5- or 6-membered heterocycles. However, due to the enaminedione structure, few successful reactions with electrophiles are known. Only if an electrophilic group is incorporated into the enaminone molecule is such intramolecular reaction observed. Enaminediones are also suitable heterodienes in 4 + 2-cycloaddition. Their electron-deficient character as heterodienes requires the use of electron-rich dienophiles. The result is a Diels-Alder reaction with inverse electron demand. 

Much larger effects of this type are observed in cycloadditions of enol ethers to tetrazines (Fig. 26), a reaction shown by Sauer and co-workers to be an example of a Diels-Alder reaction with inverse electron demand 75. The rates of 3,6-di-(2 -pyridyl)-s-tetrazine to various enol ethers and styrenes are summarized in Fig. 27. These were obtained by measuring the disappearance of the 540 nm band in the absorption spectra of the tetrazine76. These results are of particular interest, since there is little or no correspondence between the electron-donor ability of the enol ether, as measured by the ir ionization potentials (Table 5), and the rate of reaction of the enol ether. For example, although the conversion of methyl vinyl ether to 1,1-dimethoxyethylene results in a 4.3 times increase in rate, in line with the 0.2 — 0.3 eV decrease in IP, the 1,2-dimethoxyethylenes are 13 to 25 times less reactive than methyl vinyl ether, even though the IPs of these molecules are much lower... 

The hitherto unknown l-aza-3-phosphabenzenes are obtained via a regiospecific Diels-Alder reaction with inverse electron demand of 2-trifluormethyl-4-methyl-6//-l,3-oxazin-6-one with phosphaalkynes (81) or phosphaalkenes [Eq. (31)] (82). 

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