Retro-Diels/Alder reaction

The Diels-Alder reaction is reversible at elevated temperature, and therefore its products can decompose prior to evaporation by RDA reaction of the neutral in the condensed phase. The mass spectral RDA reaction has already been discussed in detail (Chap. 6.8). 

The Diels-Alder reaction is reversible under certain circumstances. 0 This reversibility can be exploited synthetically with the correct choice of diene, dienophile and reaction conditions because the equilibrium 

A classical example of a retro Diels-AIder reaction is the self condensation of cyclopentadiene (22) to give the cyclopentadienyl dimer 101. This reaction occurs quickly at temperatures 25°C, but is slow at low temperatures such as -78°C. Many Diels-AIder reactions involving cyclopentadiene are done at low temperatures with Lewis acid catalysts (sec. 11.6.A) to suppress cyclopentadiene dimerization. When heated to 160-240°C, 101 undergoes a retro-Diels-Alder reaction to generate 2 equivalents of monomeric cyclopentadiene. 

Most of the synthetic applications of retro-Diels-Alder reactions involve cyclopentadiene or furan derivatives, but there are other dienes that have appropriate functionality for this process. One example is illustrated by heating pyrone 102 in a sealed tube at 200°C with bis(trimethylsilyl)acetylene to give 103, after initial formation of cycloadduct 104 and loss of carbon dioxide via a retro-Diels-Alder reaction.The retro-Diels-Alder usually requires higher temperatures than the Diels-AIder reaction, and the normal Diels-AIder product can be obtained without competition from the retro reaction. When the retro Diels-AIder reaction is desired, flash vacuum pyrolysis is a common technique used in synthesis. Retro-Diels-Alder reactions can also be catalyzed by Lewis acids (sec. 11.6.A).An example that uses furan as a retro-Diels-Alder synthon is taken from work by Cannone et al., who used the retro-reaction as a synthetic route to 4-substituted 

Aliphatic alcohols show a strong tendency to thermally eliminate water. This is of special relevance if volatile aikanois are introduced via the reference inlet system or by means of a gas chromatograph. Then, the mass spectra correspond to the re- 

Example The El mass spectra of I-hexanol, = 102, and 1-hexene, Mr = 84, are similar because the molecular ion peak is absent in the mass spectrum of hexa-nol (Fig. 6.38). However, a more careful examination of the hexanol spectrum reveals peaks at m/z 18, 19, 31, and 45 that are absent in the hexene spectrum. These are due to H20, HsO and to oxonium ions (H2C=OH and H3CCH=OH in this case) which are reliable indicators of aliphatic alcohols and ethers (Table 6.8). 

In addition to the observation of oxonium ions, alkanols may occasionally be identified from the occurrence of a seemingly [M-3] peak while the molecular ion is absent (Fig. 6.39). The unusual difference of 3 u results from neighboring [M-CHs] and [M-H20] peaks. In these cases, a [M-33] peak indicates consecutive losses of CHs and H2O in either order, i.e., [M-H20-CH3] and [M-CH3-H20]. (Chap. 6.6.4). Alternatively, the sequence of [M-H20] and [M-H20-C2H4] may occur. 

As its name implies, the retro Diels-Alder reaction is the opposite of the Diels-Alder reaction. It is used widely in organic chemistry for the synthesis of six carbon atom rings from an alkene and a conjugated diene. An ionized cyclohexene has the chemical structure necessary for the observation of this reaction. 

FIGURE 9.30 Electron ionization mass spectra of decane (top) and dodecane (bottom). 

FIGURE 9.32 Electron ionization mass spectrum of methyl 2-methylpentanoate and McLafferty rearrangement occurring from the molecular ion leading to ion at m/z 88. 

FIGURE 9.35 Electron ionization mass spectrum of butyl propanoate and McLafferty rearrangement with double transfer of hydrogen atoms from the molecular ion. 

The generally observed endo preference has been justified by secondary orbital interactions, [17e, 42,43] by inductive or charge-transfer interactions [44] and by the geometrical overlap relationship of the n orbitals at the primary centers [45]. 

The exo-endo diastereoselectivity is affected by Lewis acid catalysts, and the ratio of two stereoisomers can be explained on the basis of the FMO theory [17e, 46]. 

The Diels Alder reaction is reversible and the direction of cycloaddition is favored because two n bonds are replaced by two cr-bonds. The cycloreversion occurs when the diene and/or dienophile are particularly stable molecules (i.e. 

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 

An example of the effect of oxide-anion associated with the 2% component (i.e. position 1, Equation 1.22) is illustrated in Equation 1.25 [53]. The potassium salt of 1,4-dihydro-1 l-hydroxy-9,10-dihydro-9,10-ethanoanthracene undergoes more facile debridging (remotion of ethylene) than the 11-deoxygenated parent compound. 

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C, b.p. 170 C (decomp.), has a characteristic odour. It is the Diels-Alder product of cyclopentadiene reacting with itself, the exo-form being formed most rapidly but the endo-form is thermodynamically favoured. At temperatures above ISO C a retro-Diels-Alder reaction occurs and cyclopentadiene monomer is regenerated see diene reactions. 

In summary, it seems that for most Diels-Alder reactions secondary orbital interactions afford a satisfactory rationalisation of the endo-exo selectivity. However, since the endo-exo ratio is determined by small differences in transition state energies, the influence of other interactions, most often steric in origin and different for each particular reaction, is likely to be felt. The compact character of the Diels-Alder activated complex (the activation volume of the retro Diels-Alder reaction is negative) will attenuate these eflfects. The ideas of Sustmann" and Mattay ° provide an attractive alternative explanation, but, at the moment, lack the proper experimental foundation. 

Analogously, the effect of micelles on the rate of the unimolecular retro Diels-Alder reaction has been studied. Also here only a modest retardation" or acceleration" is observed. Likewise, the presence of micelles has been reported to have a modest influence on an intramolecular Diels-Alder reaction . Studies on the endo-exo selectivity of a number of different Diels-Alder reactions in micellar media lead to comparable conclusions. Endo-exo selectivities tend to be somewhat smaller in micellar solutions than in pure water, but still are appreciably larger than those in organic media In contrast, in microemulsions the endo-exo selectivity is reduced significantly" ... 

The observation that in the activated complex the reaction centre has lost its hydrophobic character, can have important consequences. The retro Diels-Alder reaction, for instance, will also benefit from the breakdown of the hydrophobic hydration shell during the activation process. The initial state of this reaction has a nonpolar character. Due to the principle of microscopic reversibility, the activated complex of the retro Diels-Alder reaction is identical to that of the bimoleciilar Diels-Alder reaction which means this complex has a negligible nonpolar character near the reaction centre. O nsequently, also in the activation process of the retro Diels-Alder reaction a significant breakdown of hydrophobic hydration takes placed Note that for this process the volume of activation is small, which implies that the number of water molecules involved in hydration of the reacting system does not change significantly in the activation process. 

We conclude that the beneficial effects of water are not necessarily limited to reactions that are characterised by a negative volume of activation. We infer that, apart from the retro Diels-Alder reaction also other reactions, in which no significant reduction or perhaps even an increase of solvent accessible surface area takes place, can be accelerated by water. A reduction of the nonpolar nature during the activation process is a prerequisite in these cases. 

In the case of the retro Diels-Alder reaction, the nature of the activated complex plays a key role. In the activation process of this transformation, the reaction centre undergoes changes, mainly in the electron distributions, that cause a lowering of the chemical potential of the surrounding water molecules. Most likely, the latter is a consequence of an increased interaction between the reaction centre and the water molecules. Since the enforced hydrophobic effect is entropic in origin, this implies that the orientational constraints of the water molecules in the hydrophobic hydration shell are relieved in the activation process. Hence, it almost seems as if in the activated complex, the hydrocarbon part of the reaction centre is involved in hydrogen bonding interactions. Note that the... 

The type of enforced hydrophobic effect that is operative in the retro Diels-Alder reaction cannot be referred to an enforced hydrophobic interaction, since there is no coming together, but rather a separation of nonpolar molecules during the reaction. It is better to refer to this process as an enforced hydrophobic effect. 

Under different conditions [PdfOAcj2, K2CO3, flu4NBr, NMP], the 1 3 coupling product 86 with 4-aryl-9,10-dihydrophenanthrene units was obtained. The product 86 was transformed into a variety of polycyclic aromatic compounds such as 87 and 88[83], The polycyclic heteroarene-annulated cyclopen-tadicnc 90 is prepared by the coupling of 3-iodopyridine and dicyclopentadiene (89), followed by retro-Diels Alder reaction on thermolysis[84]. 

The reaction of o-iodophenol, norbornadiene and CO proceeds via alkene and CO insertions to afford the lactone 562, which is converted into coumarin (563) by the retro-Diels-Alder reaction. In this coumarin synthesis, norbona-diene behaves as a masked acetylene[4)3],... 

In a novel approach to vitamin K, Hoffmann-La Roche has exploited the potential acidity at C-3 as a means to attach the side chain of vitamin (36). Menadione was reacted with cyclopentadiene to yield the Diels-Alder adduct. The adduct is treated with base and alkylated at C-3 with phytyl chloride. A retro Diels-Alder reaction yields vitamin K. Process improvements in this basic methodology have been claimed by Japanese workers (37). 

HC(17)1, p. 53), and by retro-Diels-Alder reaction of the adduct from norbornadiene and fulminic acid <67AG(E)456). 

The primary and secondary products of photolysis of common diazirines are collected in Table 4. According to the table secondary reactions include not only isomerization of alkenes and hydrogen elimination to alkynes, but also a retro-Diels-Alder reaction of vibrationally excited cyclohexene, as well as obvious radical reactions in the case of excited propene. 

Molecular orbital calculations indicate that cyclo C-18 carbyne should be relatively stable and experimental evidence for cyclocarbynes has been found [25], Fig. 3B. Diederich et al [25] synthesised a precursor of cyclo C-18 and showed by laser flash heating and time-of flight mass spectrometry that a series of retro Diels-Alder reactions occurred leading to cyclo C-18 as the predominant fragmentation pattern. Diederich has also presented a fascinating review of possible cyclic all-carbon molecules and other carbon-rich nanometre-sized carbon networks that may be susceptible to synthesis using organic chemical techniques [26]. 

Scheme 9.3. Correlation between for Retro-Diels-Alder Reaction and Resonance Stabilization of Aromatic Products...

These amines gave, with methyl propiolate, products of Michael mono- and bis-addition. Adducts underwent further reaction leading to triazolo[4,5-/]quinolones 181, after retro Diels-Alder reaction and acetylene elimination to its methoxycar-... 

Retro Diels-Alder reaction of nitrogen bridgehead compound 415 at 100 °C afforded 6,7,8,9-tetrahydro-4//-pyrido[l,2-u]pyrimidin-4-one and cyclobutadiene (97SC195). 

Although furan is usually a poor diene in the Diels-Alder reaction, the chiral copper reagent 24b promotes its asymmetric addition to acryloyloxazolidinone to afford the 7-oxabicyclo[2.2.1]hept-2-ene derivative in high optical purity (Scheme 1.40). Because a retro-Diels-Alder reaction occurs above -20 °C, the reaction must be performed at low temperature (-78 °C) to obtain a high optical yield. The bicy-... 

R,R-DBFOX/Ph 250 reaction course 303 regioselectivity 216 retro-Diels-Alder reaction 29 reversal of enantioselectivity 224 rhodium... 

The Diels-Alder reaction is of wide scope. Not all the atoms involved in ring formation have to be carbon atoms the hetero-Diels-Alder reaction involving one or more heteroatom centers can be used for the synthesis of six-membered heterocycles. The reverse of the Diels-Alder reaction—the retro-Diels-Alder reaction —also is of interest as a synthetic method. Moreover and most importantly the usefulness of the Diels-Alder reaction is based on its 5y -stereospecifi-city, with respect to the dienophile as well as the diene, and its predictable regio-and c ifo-selectivities. °... 

The combination of the Diels-Alder reaction of fi-sulfonylnitroethylene and the Barton-Zard reaction provides a new synthesis of pyrroles fused with polycyclic skeletons fEq 10 31 Pyrroles fused with bicycle [3 3 3 Qctodiene are important precursors for synthesis of isoindoles via the retro Diels-Alder reaction fEq 10 33 ... 

Removal of the carbonate ring from 7 (Scheme 1) and further functional group manipulations lead to allylic alcohol 8 which can be dissected, as shown, via a retro-Shapiro reaction to give vinyl-lithium 9 and aldehyde 10 as precursors. Vinyllithium 9 can be derived from sulfonyl hydrazone 11, which in turn can be traced back to unsaturated compounds 13 and 14 via a retro-Diels-Alder reaction. In keeping with the Diels-Alder theme, the cyclohexene aldehyde 10 can be traced to compounds 16 and 17 via sequential retrosynthetic manipulations which defined compounds 12 and 15 as possible key intermediates. In both Diels-Alder reactions, the regiochemical outcome is important, and special considerations had to be taken into account for the desired outcome to. prevail. These and other regio- and stereochemical issues will be discussed in more detail in the following section. 

Deoxygenation of benzyl nitrosoformate, generated by retro-Diels-Alder reaction of its [4 + 2] cycloadduct 27 with 9,10-dimethylanthracene, with triphenylphosphane in anhydrous benzene yields the unstable benzyl 1//-azepine-1-carboxylate (28).143... 

The sequence depicted has been suggested as a plausible reaction mechanism. Diazabasketene primarily reacts via a retro-Diels-Alder reaction to give an azine which, after a Cope rearrangement, undergoes a further retro-Diels -Alder reaction to cleave off hydrogen cyanide. The resulting azabicyclo[4.2.0]octatriene finally isomerizes to the target molecule. 

A special method, with only two examples, starts from 1,2,4-triazines.20 21 Diels-Alder reaction with the strained dienophile dimethyl tricyclo[4.2.2.02,5]deca-3,7,9-triene-7,8-dicarboxylate (14) is followed by an elimination of nitrogen via a retro-Diels-Alder process. The formed product, however, cannot be isolated, but reacts via another retro-Diels-Alder reaction and an electro-cyclic reaction to provide the azocine derivative 15. The sequence order of the reactions is not clear, but both pathways lead to the same product. 

Based on the facile formation and reactivity of323, and the retro Diels-Alder reaction of 325306,310, a simple procedure has been developed for the stereoselective synthesis of functionalized conjugated dienes as well as vinylallenes311 (see equation 119). 

The ortho-quinone methides are difficult to isolate due to their high reactivity, which leads to rapid Diels-Alder dimerization or trimerization (Fig. 7.26). At 150°C, a partial retro-Diels-Alder reaction of the trimer can occur to form ortho-quinone methide and bis(2-hydroxy-3,5-dimethylphenyl) ethane (dimer).51... 

C to the thermodynamically more stable exo adduct through a retro Diels-Alder reaction followed by re-addition (Scheme 1.10). 

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. 

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