Electron-poor dienophiles

FMO theory requires that a HOMO of one reactant has to be correlated with the LUMO of the other reactant. The decision between the two alternatives - i.e., from which reactant the HOMO should be taken - is made on the basis of which is the smaller energy difference in our case the HOMO of the electron rich diene, 3.1, has to be correlated with the LUMO of the electron-poor dienophile, 3.2. The smaller this HOMO-LUMO gap, the higher the reactivity will be. With the HOMO and LUMO fixed, the orbital coefficients of these two orbitals can explain the regios-electivity of the reaction, which strongly favors the formation of 3.3 over 3.4. 

The most common and synthetically most useful Diels-Alder reactions involve the addition of an electron-rich diene and an electron-poor dienophile, e.g. 

According to Frontier Molecular Orbital (FMO) theory, Diels-Alder reaction between an electron-rich diene and an electron-poor dienophile involves interaction between the highest-occupied molecular orbital (HOMO) on the diene and the lowest-unoccupied molecular orbital (LUMO) on the dienophile. The better the HOMO/LUMO overlap and the smaller their energy difference, the more favorable the interaction and the faster the reaction. 

Experimentally, the rates of Diels-Alder reactions between electron-rich dienes and electron-poor dienophiles generally increase with increased alkyl substitution on the diene. This is because alkyl groups act as electron donors and lead to buildup of electron density on the diene. An exception to this is the reaction of Z,Z-hexa-2,4-diene with tetracyanoethylene (TCNE), which is actually slower than the corresponding addition involving E-penta-1,3-diene. 

Besides nucleophile-induced transformations the Hetero Diels-Alder (HDA) cycloaddition reactions are also very suitable ways to perform the pyrimidine-to-pyridine ring transformations. They can occur either by a reaction of an electron-poor pyrimidine system with an electron-rich dienophile (inverse HDA reactions) or by reacting an electron-enriched pyrimidine with an electron-poor dienophile (normal HDA reactions) (see Section II.B). 

The hetero Diels-Alder [4+2] cycloaddition (HDA reaction) is a very efficient methodology to perform pyrimidine-to-pyridine transformations. Normal (NHDA) and Inverse (IHDA) cycloaddition reactions, intramolecular as well as intermolecular, are reported, although the IHDA cycloadditions are more frequently observed. The NHDA reactions require an electron-rich heterocycle, which reacts with an electron-poor dienophile, while in the IHDA cycloadditions a n-electron-deficient heterocycle reacts with electron-rich dienophiles, such as 0,0- and 0,S-ketene acetals, S,S-ketene thioacetals, N,N-ketene acetals, enamines, enol ethers, ynamines, etc. 

The Diels-Alder reaction,is a cycloaddition reaction of a conjugated diene with a double or triple bond (the dienophile) it is one of the most important reactions in organic chemistry. For instance an electron-rich diene 1 reacts with an electron-poor dienophile 2 (e.g. an alkene bearing an electron-withdrawing substituent Z) to yield the unsaturated six-membered ring product 3. An illustrative example is the reaction of butadiene 1 with maleic anhydride 4 ... 

Ethylene disulfonyl-1,3-butadiene (43) is an example of an outer-ring diene with a non-aromatic six-membered heterocyclic ring containing sulfur. It is prepared by thermolysis of sulfolenes in the presence of a basic catalyst. It is very reactive [43] and even though it is electron-deficient, it readily reacted with both electron-rich and electron-poor dienophiles (Equation 2.15). 

A great acceleration was also observed in the cycloadditions of alkylidene derivatives of 5-iminopyrazoles with nitroalkenes, as electron-poor dienophiles, under MW-irradiation in solvent-free conditions [40c]. Some results are illustrated in Scheme 4.10. All the reactions took place with loss of HNO2 and/or NHMei after the cycloaddition, inducing aromatization of the final product. 

The first microwave-assisted hetero-Diels-Alder cycloaddition reaction was described by Diaz-Ortiz and co-workers in 1998 between 2-azadiene 198 and the same electron-poor dienophiles as for the preparation of pyrazolo[3,4-b]pyridines 200 (Scheme 72) [127]. These dienes reacted with... 

It has been shown that cross-coupling reactions constitute a very mild method to introduce different alkyl and aryl groups to the most active C-3 position of the pyrazinone ring [26]. The broadly functionahzed 2-azadiene system of the title compounds was studied in cycloaddition reactions with various electron-reach and electron-poor dienophiles to provide highly substituted heterocycles [24]. 

Kahn and Hehre straightforwardly extended this idea to the description of Jt-facial selectivity in Diels Alder reactions. They simply stated cycloaddition involving electron-rich dienes and electron-poor dienophiles should occur preferentially onto the diene face which is the more nucleophilic and onto the diene face which exhibits the greater electrophihcity (Scheme 40) [49],... 

Mataka and coworkers reported the studies of the Diels-Alder reactions of [3.3] orthoanthracenophanes 96 and 97, of which anthraceno unit, the potential diene, has two nonequivalent faces, inside and outside. The reactions of 96 with dien-ophiles gave the mixtures of inside and outside adducts with the ratios between 1 1 and 1 1.5. However, the ratio changes drastically, in favor of the inside adducts, when 97 reacts with dienophiles such as maleic anhydride, maleimide and naphto-quinone [55] (Scheme 46). Mataka suggested that the Jt-facial selectivity is controlled by an orbital interaction between the electron-poor dienophiles and the Jt-orbital of the facing aromatics, which would lead to a stabilization of the transition state, while Nishio suggested that the selectivity is due to the attractive k/k or CH/jt interaction [53]. 

Diels-Alder reactions in supercritical water have also been investigated.57 Kolis has shown that Diels-Alder reactions of dienes with various electron-poor dienophiles can be performed in supercritical water with high yields of the desired product without the addition of... 

Diels-Alder cycloaddition reactions of electron-poor dienophiles to electron-rich dienes, which are generally carried out thermally, afford widespread applications for C—C bond formation. On the basis of their electronic properties, numerous dienes can be characterized as electron donors and dienophiles as electron acceptors. Despite the early suggestions by Woodward,206 the donor/ acceptor association and electron-transfer paradigm are usually not considered as the simplest mechanistic formulation for the Diels-Alder reaction. However, the examples of cycloaddition reactions described below will show that photoirradiation of various D/A pairs leads to efficient cycloaddition reactions via electron-transfer activation. 

Hexamethyl[3]radialene (25) does not undergo Diels-Alder-reactions with the typical electron-poor dienophiles, probably because of the full substitution at the diene termini. With TCNE, however, a violet-blue charge-transfer complex is formed which disappears within 30 min at room temperature to form a 1 1 adduct (82% yield) to which structure 55 was assigned9. Similar observations were made with tris(2-adamantylidene)cyclopropane (34), but in this case cycloaddition product 56 (81% yield) was identified its allenic moiety is clearly indicated by IR and 13C NMR data12. 

Zwitterionic intermediates have been reported for reactions of strongly electron-rich 1,3-butadienes, e.g. 1,1-dimethoxy-1,3-butadiene, with strongly electron-poor dienophiles46. In the reactions of l,4-bis(dimethylamino)-1,3-butadiene with strongly electron-poor dienophiles, electron transfer from the diene to the dienophile was reported to occur47. 

The main stabilization in reactions with activated reaction partners, viz. when one partner is electron-rich and the other electron-poor, arises through interaction between the donor HOMO and the acceptor LUMO which are much closer in energy than the acceptor HOMO and the donor LUMO. Figure 2 illustrates which interactions between the frontier orbitals cause the main stabilization in normal, neutral and inverse Diels-Alder reactions. For example, the main stabilization in the reaction between an electron-rich diene and an electron-poor dienophile stems from the interaction of the diene HOMO with the dienophile LUMO. 

The presence of electron-donating substituents in the diene enables it to react with simple aldehydes thus both acetaldehyde and benzaldehyde add to 1-methoxy-1,3-butadiene at 50-65 °C under high pressure (20 Kbar) to give dihydropyrans as 70 30 mixtures of cis- and frans-isomers (equation 5)4. The combination of electron-rich diene/electron-poor dienophile makes it possible to perform the reaction under milder conditions. 2-Alkyl-l-ethoxy-1,3-butadienes and diethyl mesoxalate afford dihydropyrans almost quantitatively (equation 6)5. 

The interactions of the occupied orbitals of one reactant with the unoccupied orbitals of the other are described by the third term of the Klopman-Salem-Fukui equation. This part is dominant and the most important for uncharged reaction partners. Taking into account that the denominator is minimized in case of a small energy gap between the interacting orbitals, it is clear that the most important interaction is the HOMO-LUMO overlap. With respect to the Diels-Alder reaction, one has to distinguish between two possibilities depending on which HOMO-LUMO pair is under consideration. The reaction can be controlled by the interaction of the HOMO of the electron-rich diene and the LUMO of the electron-poor dienophile (normal electron demand) or by the interaction of the LUMO of an electron-poor diene and the HOMO of an electron-rich dienophile (inverse electron demand cf Figure 1). 

As a result of its reduced aromaticity, relative to pyrrole, furan undergoes [4 + 2] cycloaddition reactions much more readily. It combines as a diene with electron-poor dienophiles to yield Diels-Alder-type adducts. Maleic [(Z)-butenedioic acid] anhydride, for example, reacts at room temperature, and the only isolated adduct is the exo isomer (the more thermodynamically favoured adduct) (Scheme 6.27a). 

Nitro-2-phenyloxazole 271a undergoes Diels-Alder [4 + 2] cycloaddition with both electron-rich and electron-poor dienophiles to give an oxazoline 273 that may not be isolable due to the facile aromatization to a fused oxazole 274. Examples are shown in Table 8.22 (Scheme 8.77). 

The pioneer work on this subject using simple 1-azadienes is due to Ghosez et al. (82TL3261 85JHC69) they succeeded in reacting 1-azadienes as 47r-electron components in Diels-Alder cycloadditions. Thus, l-dimethylamino-3-methyl-l-azabuta-l,3-diene (a,/3-unsaturated hydrazone) 54 did undergo [4 + 2] cycloaddition to typical electron-poor dienophiles, e.g., methyl acrylate, dimethyl fumarate, acrylonitrile, maleic anhydride, and naphthoquinone, producing pyridine derivatives 55-57 (Scheme 14). 

We were not able to obtain any cycloadduct from unactivated 2-azadienes 139 and esters of acetylenedicarboxylic acid. However, we found that 139 did cycloadd to typical electron-poor dienophiles such as esters of azodicarboxylic acid and tetracyanoethylene (Scheme 62). Thus, diethyl and diisopropyl azodicarboxylates underwent a concerted [4 + 2] cycloaddition with 139 to afford in a stereoselective manner triazines 278 in 85-90% yield (86CC1179). The minor reaction-rate variations observed with the solvent polarity excluded zwitterionic intermediates on the other hand, AS was calculated to be 48.1 cal K 1 mol-1 in CC14, a value which is in the range of a concerted [4 + 2] cycloaddition. Azadienes 139 again reacted at room temperature with the cyclic azo derivative 4-phenyl-1,2,4-triazoline-3,5-dione, leading stereoselectively to bicyclic derivatives 279... 

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. 

This and other similar cycloadditions, however, when unactivated hydrocarbons without heteroatom substituents participate in Diels-Alder reaction, are rarely efficient, requiring forcing conditions (high temperature, high pressure, prolonged reaction time) and giving the addition product in low yield. Diels-Alder reactions work well if electron-poor dienophiles (a, p-un saturated carbonyl compounds, esters, nitriles, nitro compounds, etc.) react with electron-rich dienes. For example, compared to the reaction in Eq. (6.86), 1,3-butadiene reacts with acrolein at 100°C to give formy 1-3-cyclohexene in 100% yield. 

Support-bound pyridines and partially saturated pyridines can be valuable synthetic intermediates, enabling various types of chemical transformation. Piperidinones can be prepared on cross-linked polystyrene by the addition of organometallic reagents to tetrahydropyridinones (Entry 10, Table 15.23). 1,2-Dihydropyridines are electron-rich dienes that can undergo Diels-Alder reaction with electron-poor dienophiles. Diels-Alder cycloaddition of support-bound 1,2-dihydropyridines has been used to prepare nitrogen-containing polycyclic systems (Entry 12, Table 15.23). 

Azabutadiene, CH2=N-CH=CH2/ is an electron-poor compound its orbitals are lower lying than those of butadiene. Experiments show that electron-poor dienophiles are completely unreactive toward A, but those which are electron-rich give Diels-Al-der adducts 57... 

Analogous calculations give a + 0.549)8and a — 0.494)8for 2-azabutadiene. Since the HOMO-LUMO gap is smaller in the latter case, 2-azabutadiene is more reactive. The reactivity difference will be accentuated in reactions with electron-poor dienophiles. 

The reaction with 1-azabutadiene is also unfavorable for other reasons. To begin with, the 4 + 2 cyclization is inherently less exothermic than with 2-azabutadiene (see Exercise 20, p. 123). Furthermore, the enamine product will rapidly undergo side-reactions with adventitious electrophiles. An imine-enamine tautomerism which transforms R-N=CH-CH=CH-CH3 into RNH-CH=CH-CH=CH2 also contributes to lowering the yield. Finally, electron-poor dienophiles may undergo a competing reaction with the nitrogen lone pair. 

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