Alkenes, electronic effects Diels-Alder reaction

The Diels-Alder reaction is defined as a [4-1-2] cycloaddition between a conjugated diene and a substituted dienophile (alkene or alkyne) to form a (hetero-)cyclohexene system. Based on the electronic effects of the substituent on the diene and dienophile, Diels-Alder reactions can be classified as normal electron-demand (electron-rich diene reacts with electron-deficient dienophile) or inverse electron-demand (iEDDA, electron-deficient diene reacts with electron-rich dienophile) reactions (Scheme la). In a normal electron-demand Diels-Alder reaction, the electron-deficient dienophile, typically a Michael acceptor, is likely to be attacked by endogenous nucleophiles such as free amino and thiol groups in vivo. For this reason, the use of this reaction in bioorthogonal chemistry apphcations poses a challenge. 

For the ordinary Diels-Alder reaction the dienophile preferentially is of the electron-poor type electron-withdrawing substituents have a rate enhancing effect. Ethylene and simple alkenes are less reactive. Substituent Z in 2 can be e.g. CHO, COR, COOH, COOR, CN, Ar, NO2, halogen, C=C. Good dienophiles are for example maleic anhydride, acrolein, acrylonitrile, dehydrobenzene, tetracya-noethylene (TCNE), acetylene dicarboxylic esters. The diene preferentially is of the electron-rich type thus it should not bear an electron-withdrawing substituent. 

Cyclopentadienylindium(I) has been shown to be effective in the reaction with aldehydes or electron-deficient alkenes to form highly functionalized cyclopentadienes in aqueous media (See Section 8.4.3).101 This reaction with the appropriate substrates can be followed by an intramolecular Diels-Alder reaction in the same pot to provide complex tricyclic structures in a synthetically efficient manner (Scheme 12.4). 

Diels-Alder catalysis.1 This radical cation can increase the endo-selectivity of Diels-Alder reactions when the dienophile is a styrene or electron-rich alkene. This endo-selectivity obtains even in intramolecular Diels-Alder reactions. Thus the triene 2, a mixture of (Z)- and (E)-isomers, cyclizes in the presence of 1 to 0° to the hydroindanes 3 and 4 in the ratio 97 3. Similar cyclization of (E)-2 results in 3 and 4 in the ratio 98 2 therefore, the catalyst can effect isomerization of (Z)-2 to (E)-2. Even higher stereoselectivity is observed when the styrene group of 2 is replaced by a vinyl sulfide group (SC6H5 in place of QHtOCT ). 

Diels-Alder reactionsBoth 1,4-dicyanonaphthalene (DCN) and 2,6,9,10-te-tracyanoanthracene (TCA) have been used as sensitizers to effect photochemical [4 + 2]cycloadditions of electron-rich dienes and electron-rich dienophiles, which do not normally undergo thermal cycloadditions. These cycloadditions are known as triplex Diels-Alder reactions because they are postulated to involve as an intermediate a three-membered complex of sensitizer, dienophile, and diene. This reaction is useful for synthesis of bicyclo[2.2.2]octenes from some silyl enol ethers, alkenes, or arylalkynes. 

The Diels-Alder reaction is called a [4 + 2] cycloaddition because a ring is formed by the interaction of four pi electrons in the diene with two pi electrons of the alkene or alkyne. Since the electron-poor alkene or alkyne is prone to react with a diene, it is called a dienophile ( lover of dienes ). In effect, the Diels-Alder reaction converts two pi bonds into two sigma bonds. We can symbolize the Diels-Alder reaction by using... 

The selective formation of the ene adduct with the methoxycarbonyl group endo is analogous to the endo selectivity usually observed in the Diels-Alder reaction, probably for similar electronic reasons. With 1,2-disubstituted and trisubstituted alkenes the endo selectivity of this ene reaction controls the relative stereochemistry of two centers in a 1,3-relationship. Since attempted thermal ene reactions of methyl a-haloacrylates give only polymer, the effect of the Lewis acid on the stereochemistry cannot be determined. 

The addition of a C-2 (equation 1 R = H > alkyl, aryl > OMe NR2), C-3, or C-4 electron-donating substituent to a 1 -oxa-1,3-butadiene electronically decreases its rate of 4ir participation in a LUMOdiene-controlled Diels-Alder reaction (c/. Table 5). Nonetheless, a useful set of C-3 substituted l-oxa-l,3-buta-dienes have proven to be effective dienes ° and have been employed in the preparation of carbohydrates (Table 6). The productive use of such dienes may be attributed to the relative increased stability of the cisoid versus transoid diene conformation that in turn may be responsible for the Diels-Alder reactivity of the dienes. Clear demonstrations of the anticipated [4 + 2] cycloaddition rate deceleration of 1-oxa-1,3-butadienes bearing a C-4 electron-donating substituent have been detailed (Table 6 entry 4). >> "3 In selected instances, the addition of a strong electron-donating substituent (OR, NR2) to the C-4 position provides sufficient nucleophilic character to the 1-oxa-1,3-butadiene to permit the observation of [4 + 2] cycloaddition reactions with reactive, electrophilic alkenes including ketenes and sul-fenes, often in competition with [2 + 2] cycloaddition reactions. ... 

One of the most effective approaches to implementing the Diels-Alder participation of 1-oxa-1,3-butadienes is through the use of an intramolecular [4 + 2] cycloaddition reaction.A select set of thermal and Lewis acid-catalyzed intramolecular cycloaddition reactions of unactivated and electron-rich alkenes with a,P-unsaturated aldehydes and ketones has been detailed. Two examples of the poorly matched intramolecular Diels-Alder reaction of an a,P-unsaturated aldehyde (4 ir component) with an a, 3-unsaturated amide (2ir component) have proven successful (190-160 °C) and may be attributed to the entropic assistance provided by the intramolecular reaction. These observations have been applied in... 

The first disconnection lib (reductive amination) takes no consideration of the chirality at all - we will worry about this later. We already have a six membered ring and it now contains all the chirality. The introduction of double bonds by FGA is used to considerable effect in this retro-synthesis. The first new alkene allows us to do an aldol disconnection 13 that not only removes a carbon chain but also reveals an electron-withdrawing group on the six-membered ring 14. This is, of course, one vital component of the Diels-Alder reaction. The next FGA puts in the double bond that allows us to do the retrosynthetic Diels-Alder step 15. 

The most important type of thermal [4+2]-cycloaddition reactions is known as the Diels-Alder reaction, as this reaction was discovered by Otto Paul Herman Diels and Kurt Alder in 1928 [19]. It may be noted that both of them awarded the Nobel Prize in Chemistry in 1950 for their contributions on the development of the Diels-Alder reaction. These reactions are defined as the concerted [4+2]-cycloaddition reactions of conjugated dienes with an alkene or alkyne. The alkene or alkyne is known as dienophile. Hence, these reactions are described as [jt" +jt ]-cycloaddition reactions. These reactions are carried out by heating the compounds alone or in an inert solvent or in the presence of a Lewis acid. An alkene or alkyne having electron-withdrawing substituent acts as an effective dienophile. These reactions proceed stereospecificaUy to syn-addition with respect to both diene and dienophile. 

Reactive Enophile in [4 + 2] Cycloadditions. Vinylketenes are not effective as dienes in Diels-Alder reactions because they undergo only [2 + 2] cycloaddition with alkenes, as predicted by frontier molecular orbital theory. However, silylketenes exhibit dramatically different properties from those found for most ketenes. (Trimethylsilyl)vinylketene (1) is a relatively stable isolable compound which does not enter into typical [2 + 2] cy do additions with electron-rich alkenes. Instead, (1) participates in Diels-Alder reactions with a variety of alkenic and alkynic dienophiles. The directing effect of the carhonyl group dominates in controlling the regiochemical course of cycloadditions using this diene. For example, reaction of (1) with methyl propiolate produced methyl 3-(trimethylsilyl)sahcylate with the expected regiochemical orientation. ProtodesUylation of this adduct with trifluoroacetic acid in chloroform (25 °C, 24 h) afforded methyl salicylate in 78% yield (eq 2). 

The Diels-Alder reaction is a cycloaddition between a diene, in this case the ethyl sorbate, and a dienophile, usually an electron-poor alkene (Section 14-8). We should first have a look at the two reaction partners to visualize the new bonding connections that this process will effect. To do so, we need to rotate about the single bond between carbon 3 and carbon 4 of ethyl sorbate to place its double bonds in the necessary conformation. We do this carefully, so as not to mistakenly change the stereochemistry of the double bonds They both start out trans and must be that way after we have finished. Next, we connect the ends of the diene system to the carbon atoms of the dienophile s... 

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