Electron deficient Diels-Alder reactions

Sauer and Heldmann [97] recently reported an interesting application of ethynyltributyltin as an electron-rich dienophile in an inverse electron-demand Diels-Alder reaction with the electron-deficient triazine derivative 94. This method is interesting because the reaction is highly regioselective and the trialkylstannyl group is easily replaced by several groups under mild conditions, leading to substituted pyridines 95 (Scheme 2.41). 

Diels-Alder cycloadditions involving norbomene 57 [34], benzonorbomene (83), 7-isopropylidenenorbomadiene and 7-isopropylidenebenzonorbomadiene (84) as dienophiles are characterized as inverse-electron-demand Diels-Alder reactions [161,162], These compounds react with electron-deficient dienes, such as tropone. In the inverse-electron-demand Diels-Alder reaction, orbital interaction between the HOMO of the dienophile and the LUMO of the diene is important. Thus, orbital unsymmetrization of the olefin it orbital of norbomene (57) is assumed to be involved in these top selectivities in the Diels-Alder cycloaddition. 

In work reminiscent of earlier studies by van der Plas <89T803, 89T5611>, Dehaen and co-workers illustrated how the electron deficient pyrimidine ring can be exploited in the intramolecular inverse electron demand Diels-Alder reactions of pyrimidine-tethered alkynes 102 <00SL625>. Under thermal conditions, pyridines 103 were produced in modest to excellent yields. 

Conjugated oximes were converted to pyrazoles in a one-pot reaction by refluxing with hydrazine and iodine in ethanol. The process proceeds via an inverse electron-demand Diels-Alder reaction involving electron-deficient heterodienes and diimide species as dipolarophiles . ... 

The reactivity of the produced complexes was also examined [30a,b]. Since the benzopyranylidene complex 106 has an electron-deficient diene moiety due to the strong electron-withdrawing nature of W(CO)5 group, 106 is expected to undergo inverse electron-demand Diels-Alder reaction with electron-rich alkenes. In fact, naphthalenes 116 variously substituted at the 1-, 2-, and 3-positions were prepared by the reaction of benzopyranylidene complexes 106 and typical electron-rich alkenes such as vinyl ethers, ketene acetals, and enamines through the Diels-Alder adducts 115, which simultaneously eliminated W(CO)6 and an alcohol or an amine at rt (Scheme 5.35). 

PREPARATION AND INVERSE ELECTRON DEMAND DIELS-ALDER REACTION OF AN ELECTRON-DEFICIENT HETEROCYCLIC AZAOIENE TRIETHYL 1.2,4-TRIAZINE-3,5,6-TRICARBOXYLATE (l,2,4-Triazine-3,5,6-tricarbo orl 1c acid, triethyl ester)... 

Very few methods exist for the stereoselective synthesis of fused bicyclic sulfonamides. One example, developed by Tozer and co-workers, involves an inverse electron demand Diels-Alder reaction (Equation 34 Table 4) <20010L369>. Electron-deficient sulfonamide trienes 216, which are prepared in a few steps from V-BOC-protected methanesulfonamide, react slowly at high temperature in a sealed tube to produce m-217 as the major isomeric cycloadduct (BOG = /-butoxycarbonyl). 

The Pechmann and Knoevenagel reactions have been widely used to synthesise coumarins and developments in both have been reported. Activated phenols react rapidly with ethyl acetoacetate, propenoic acid and propynoic acid under microwave irradiation using cation-exchange resins as catalyst <99SL608>. Similarly, salicylaldehydes are converted into coumarin-3-carboxylic acids when the reaction with malonic acid is catalysed by the montmorillonite KSF <99JOC1033>. In both cases the use of a solid catalyst has environmentally friendly benefits. Methyl 3-(3-coumarinyl)propenoate 44, prepared from dimethyl glutaconate and salicylaldehyde, is a stable electron deficient diene which reacts with enamines to form benzo[c]coumarins. An inverse electron demand Diels-Alder reaction is followed by elimination of a secondary amine and aromatisation (Scheme 26) <99SL477>. 

This procedure describes the preparation and inverse electron demand (LUM0(jjene controlled/ Diels-Alder reaction of an electron-deficient diene. While extensive studies on the preparative utility of the normal (HOMOjjg controlled) Diels-Alder reaction have been detailed, few complementary studies on the preparative value of the inverse electron demand Diels-Alder reaction have been described. Table I details representative 3-carbomethoxy-2-pyrones which have been prepared by procedures similar to that described herein and Tables II and III detail their inverse electron demand Diels-Alder reactions with electron-rich dienophiles. 

It is also worth mentioning that inverse electron demand Diels-Alder reactions are possible with pyran-2-ones and coumarins. Shown in Equation (26) is one such reaction using an electron-deficient diene of coumarin 258 with enamine 259 to give 260 <1999SL477>. 

Thus, Ghosez et al. were successful in showing that A,iV-dimethyl hydrazones prepared from a,/3-unsaturated aldehydes react smoothly in normal electron demand Diels-Alder reactions with electron-deficient dienophiles [218, 219]. Most of the more recent applications of such 1-aza-l,3-butadienes are directed towards the synthesis of biologically active aromatic alkaloids and azaanthra-quinones [220-224] a current example is the preparation of eupomatidine alkaloids recently published by Kubo and his coworkers. The tricyclic adduct 3-19 resulting from cycloaddition of naphthoquinone 3-17 and hydrazone 3-18 was easily transformed to eupomatidine-2 3-20 (Fig. 3-6) [225]. 

Similarly to the homologous 1-oxa-1,3-butadienes, 1-thia-1,3-butadienes are known to be very suitable and reactive substrates for hetero Diels-Alder reactions. However, in contrast to the oxa-1,3-butadienes which in general act as electron-deficient component in such cycloadditions, thia-1,3-butadienes predominantly undergo normal electron demand Diels-Alder reactions with electron-deficient dienophiles. Nevertheless, also some reactions of thia-1,3-butadienes involving electron-rich dienophiles have been described [412,413], Thia-1,3-butadienes considerably tend to dimerize due to their high reactivity in hetero Diels-Alder reactions [414]. 

PREPARATION AND INVERSE ELECTRON DEMANO DIELS-ALDER REACTION OF AN ELECTRON-DEFICIENT DIENE METHYL 2-OXO-5, 6, 7, 8-TETRAHYDRO-ZH-l-BEN 2DPYRAN-3-CARBOXYLATE... 

The inverse electron demand Diels-Alder reaction between enamines and electron-deficient dienes is a useful method for the synthesis of six-membered rings. The process is considered LUMOdiene-controlled70 72, and its rate (as in the other Diels-Alder... 

There is also a small number of [4 + 2] cycloadditions involving electron-rich dienophiles e.g. en-amines, vinyl ethers and vinyl sulfi s) and electron-deficient dienes. These inverse-electron-demand Diels-Alder reactions correspond to a predominant dienophile-HOMO/diene-LUMO overlap. 

An interesting example of an asymmetric inverse-electron-demand Diels-Alder reaction is the smooth addition of chiral vinyl ether (436) (readily accessible from 435) to the electron-deficient 3-to-... 

Neunhoeffer and Wiley (78HC226) discovered that 1,2,4-triazine served as a reactive, electron-deficient diene in inverse electron demand Diels-Alder reactions with electron-rich or strained olefins. Cycloaddition occurs exclusively across C-3/C-6 of the triazine nucleus and there is a strong preference for the nucleophilic carbon of the dienophile to be attached to C-3... 

The thermal [4+2] Diels-Alder cycloaddition reaction can be classified into three processes the normal Diels-Alder reaction of electron-rich dienes with electron-deficient dienophiles (HOMOdiene-controlled), the neutral Diels-Alder reaction and the inverse electron-demand Diels-Alder reaction of electron-deficient dienes with electron-rich dienophiles (LUMOdiene-controlled). 

Heteroaromatic systems that possess an electron-deficient azadiene are ideally suited for participation in inverse electron-demand Diels-Alder reactions. Additional substitution of the heterocyclic azadiene system with electron-withdrawing groups accents the electron-deficient nature of the heterodiene and permits the use of electron-rich, strained or even simple olefins as dienophiles. 

Thus, the electron-deficient 1,2,4,5-tetrazine 7 reacts smoothly with the electron-rich acetylene 8 in an inverse electron-demand Diels-Alder reaction First, the [4+2] cycloaddition of 7 with 8 takes place and then the formed intermediate 9 loses N2 to provide the symmetrical 1,2-diazine 6. 

The reaction is clearly a cycloaddition but at first sight the regioselectivity is all wrong. The answ comes from a realization that this is a reverse electron demand Diels-Alder reaction. The diene very electron-deficient with two conjugated carhonyl groups so the dienophile needs to be electro." rich. The enone is not electron-rich enough but its enol is. The enone could be prepared by Eire reduction... 

In electron-demand Diels-Alder reactions, dienes are activated by electron-donating substituents, such as alkyl, -NR2, and -OR. Electron-rich dienes accelerate the reaction with electron-deficient dienophiles, as illustrated by the relative reactivity trend shown below. 

This approach to 1,2-diazine and pyrrole introduction based on the inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate complements the [4 + 2] cycloaddition reactions of a range of electron-deficient heterocyclic azadienes which permits the divergent preparation of a range of heterocyclic agents employing a common dienophile precursor, Scheme I. 

Hetero-Diels-Alder reactions are not as straightforward as ordinary Diels-Alder reactions. In an ordinary (normal electron demand) Diels-Alder reaction we are accustomed to having an electron-rich diene and an electron-deficient dienophile. In asymmetric catalysis, early successes with a hetero-Diels-Alder reaction58 typically needed a very electron rich diene, such as Danishefsky s diene 248, or very electron deficient dienophiles like a glyoxylate 249. 

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