Retro Diels—Alder cycloreversion

An interesting one-pot, five-component domino process using an intermolecular Diels-Alder reaction of furans with AT-phenylmaleimide as its final step has been used to construct the central core of indolo[2,3- ]carbazoles (Equation 86) <2002AGE4291>. Thus, aminooxazoles produced from an Ugi three-component reaction undergo acylation/intramolecular Diels-Alder/retro-Diels-Alder cycloreversion with pentafluorophenyl arylprop-2-ynoates to give furan derivatives. Subsequent Diels-Alder cycloaddition at elevated temperatures with A -phenylmaleimide produces carbazoles in good yields (Table 5). 

The application of reversible click reactions, such as Cu-catalyzed azide-aUcyne addition, Michael-type addition, and retro Diels—Alder cycloreversion, is used as a simple approach to perform a degradation process under physiological conditions. This class of reversible chck reaction is promising for predictable, tunable control of cell microenvironment properties. 

Second step is retro Diels-Alder cycloreversion of o s+o s+ic st3 e which is allowed thermally. T.S. of second step contains 6-electrons and 0-node, therefore, is aromatic predicting reaction is thermally allowed. 

The retro Diels-Alder reaction usually requires high temperatures in order to surmount the high activation barrier of the cycloreversion. Moreover, the strategy of retro Diels-Alder reaction is used in organic synthesis to mask a diene fragment or to protect a double bond [47]. Some examples are illustrated in Scheme 1.11. 

The retro Diels-Alder reaction is strongly accelerated when an oxide anion substituent is incorporated at positions 1 and 2 of the six-membered ring which has to be cycloreversed, namely at one terminus carbon of the original diene or at one sp carbon of the dienophile [51] (Equation 1.22). 

The first example of an oxide-anion accelerated retro Diels Alder reaction was reported by Papies and Grimme [52]. The adduct 19 (Equation 1.23) treated with tetra-w-butylammonium fluoride (TBAF) in THE at room temperature is immediately converted into 20, in contrast to the parent 21 (Equation 1.24) which undergoes cycloreversion into 22 at 100 °C. The dramatic oxide-anion acceleration (> 10 ) was ascribed to the loss of basicity of about 8pK, units in the transformation of alcoholate ion of precursor 19... 

A somewhat milder route which appears to be devoid of the complications of isomerization is the retro-Diels-Alder reaction of bicyclo [2.2.2] octadienes, frequently substituted with aryl groups (5,30,53,65), [Eq. (2)], and recently Wiberg (88,90) described a very mild route involving both [2 + 2] and [2 + 4] cycloreversions which occur at 60°C to generate Me2Si=C(SiMe3)2. However, the generality of this latter source of silenes has not been established yet [Eq. (3)]. 

Retro-Diels-Alder reactions can be used to regenerate dienes or alkenes from Diels-Alder protected cyclohexene derivatives under pyrolytic conditions144. Most of the synthetic utility of this reaction comes from releasing the alkene by diene-deprotection. However, tetralin undergoes cycloreversion via the retro-Diels-Alder pathway to generate o-quinodimethane under laser photolysis (equation 89)145. A precursor of lysergic acid has been obtained by deprotection of the conjugated double bond and intramolecular Diels Alder reaction (equation 90)146. 

An even more pronounced retro-Diels-Alder reaction occurs by using 1,3-di-phenylisobenzofuran (DPIF), 9-methylanthracene or 9,10-dimethylanthracene as dienes [8, 10-12]. The monoadduct of DPIF cannot be isolated from the reaction mixture, while the monoadduct of the 9-methyl- or 9,10-dimethyl- derivatives of anthracene can be isolated at temperatures lower than room temperature [10]. Both anthracene derivatives decompose at room temperature, the adduct with one methyl group within hours, the adduct with two methyl groups within minutes. For DPIF and the anthracene compounds the retro-Diels-Alder reaction seems to be facilitated by steric repulsion due to the bulky groups. However, as shown by Wudl and coworkers [13], the cycloadduct of with isobenzofuran (Scheme 4.2), which was generated in situ from l,4-dihydro-l,4-epoxy-3-phenylisoquinoline, is stable in the solid state as well as in solution and shows no tendency to undergo cycloreversion. 

These examples already prove that the potential of such reactions for the synthesis of stable fuUerene derivatives is restricted due to the facile cycloreversion to the starting materials. Nevertheless, cycloreversion can also be useful. Reversibility of dimefhylanthracene addition was utilized for the selective synthesis of Ti -symme-trical hexakisadducts (see Chapter 10) [12]. In another example, a dendritic polyamidoamine-addend was reversibly attached to via an anthracene anchor (Figure 4.1) [14, 15]. The dendrofullerene, which is soluble in polar solvents, can be obtained in 70% yield and the retro-Diels-Alder reaction at 45 °C proceeds with a conversion rate of more than 90%. 

Thermal cycloreversion of the adducts can be accomplished at a convenient rate when heated in toluene under reflux. If a new diene is present in the reaction mixture, the thioaldehyde thus generated in the retro-Diels-Alder reaction may give a new adduct. Therefore, adducts 81 and 82 act as thioaldehyde or thioketone transfer reagents. These adducts dissociate reversibly on heating, thus ensuring that the concentration of the labile species remains very low. For this reason, polymerization is not a serious problem especially in the case of thioaldehydes224. The transient thiocarbonyl compounds can be trapped not only by dienes but also by 1,3-dipolar cycloadditions332 (equation 85). 

Cycloalkenones.3 Cycloalkenones can be prepared by a retro Diels-Alder reaction of norbornenes of type 1, conducted at 25-70° in the presence of CH3A1C12 (1 equiv.) and a reactive dienophile, usually maleic anhydride or fumaronitrile. The [4 + 2]cycloreversion was used to prepare 12-oxophytodienoic acid (4), which epi-merizes at Cu to the trans-isomer on brief exposure to acid. The precursor nor-bornene 3 was prepared from the known dienone 2 as shown. Treatment of 3 at room... 

Irradiation of the triazoline (70) in methanol gave the ester (71) via the ketene (72), formed by a retro-Diels-Alder rearrangement as shown in Scheme An analogous cycloreversion has been reported in azatricyc-... 

The reaction of the unstable intermediate is called a cycloreversion of retro-Diels-Alder reaction. Ordinarily it is designated by considering the reverse cycloaddition of the products of the reaction. 

Cycloadditions are reversible. These cycloreversions (for example, the retro-Diels-Alder reaction) follow the same symmetry rules as cycloadditions—as they must, of course, since they occur via the same transition states. 

Thermal fragmentation of maleic hydrazide in the range of 450°-800°C proceeds by two pathways (a) (2+2+2)-cycloreversion to give acetylene and isocyanic acid as primary products, and (b) a retro-Diels-Alder reaction to give initially diimide and a bisketene. ... 

The reaction types known to produce disilenes are summarized in Chart 1 and apply regardless of the ultimate stability of the product. Historically, thermal 4 + 2 cycloreversion of complex l,2-disilacyclohex-4-enes, i.e. a retro-Diels-Alder fragmentation came first8 -14, followed by silylene dimerization15 -17. This early work produced only indirect evidence for the formation of disilenes as reactive intermediates, but in retrospect it is clear that these species were indeed produced. The early history of the subject is discussed in Reference 1. The first directly observable and isolable disilene resulted from the dimerization of photochemically produced dimesitylsilylene18, ushering in a new era in disilene chemistry. These more recent developments are described in Reference 2. 

As a rule, the initial hetero-DiELS-ALDER adduct 2 cannot be isolated. It eliminates N2 in a retro-DiELS-Alder reaction and is converted into a 4,5-dihydropyridazine 3. This can be stabilized as a 1,4-dihydropyridazine 7 (especially if X = H) by a 1,5 hydrogen shift or (if X = OR and NR2) as the pyridazines 5 and 6 by dehydrogenation or HX elimination. As a diazadiene, it can also engage in a further Diels-Alder reaction with excess of alkene 3delding the stable 2,3-diazabicyclo[2.2.2]oct-2-ene 4. The initial Diels-Alder product tetraazabicyclo[2.2.2]octatriene 8, which arises from the reaction between alkynes and 1,2,4,5-tetrazines, undergoes a cycloreversion with N2 elimination affording the pyridazine 6. With nitriles, 1,2,4-triazines 9 are obtained. 

The retro Diels-Alder reaction (cycloreversion) under mild conditions can be used for the preparation of pyridazines. Bridged 1,4-epimino-naphthalenes 172 react readily with 3,6-di(2-pyridyl)-s-tetrazine 173 in an exothermic reaction involving nitrogen elimination to yield pyridazines 176 (2003COR1423 Scheme 31). 

Retro-Diels-Alder Reaction Cyclohexene (Figure 6.7) and its derivatives undergo a retro-Diels-Alder (RDA) reaction upon El, which is a special case of the cycloreversion reaction [27,28]. This reaction is the reverse of a well-known [4 -h 2] cycloaddition reaction between a conjugated diene and an olefin, named the Diels-Alder reaction, after its discoverers. The impetus for the RDA reaction is the ring double bond, which upon ionization creates a radical site and a charge site ... 

Cycloreversion reactions, especially the retro-Diels-Alder reaction, also yield diagnostic product ions. Fragmentation reactions of each class of compounds (e.g., alkanes, ketones, alcohols, esters) are also discussed (Section 6.6). Upon El, each class of molecules fi agments in a typical fashion that can identify the precursor structure. 

The outstanding SM behavior was restored after recychng of the corresponding system. Note that recycling means cycloreversion here, that is, onset of the retro Diels-Alder reaction at T > 105 C (Figure 6.4). Note that the anthracene end functionalization, instead of furan, was foreseen to influence the kinetics of the adduct formation and its temperature stabihty. 

Recent developments in the retro-Diels-Alder reaction have been reviewed. 1,3-Dipolar cycloadditions of nitrile oxides to 4-aryl-2-alkyIthio-l-azetines gave oxadiazabicyclo[3.2.0]heptenes that undergo a 2 -i- 2-cycloreversion with the loss of a styrene to furnish 5-alkylthio-3-aryl-l,2,4-oxadiazoles (Scheme 1). ... 

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