Retro-Diels-Alder reaction requirements

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. 

Retro Diels-Alder reactions often require severe conditions, high temperatures, and, sometimes, flash vacuum thermolysis. Microwave irradiation has been used as an alternative to these harsh conditions [12], even using graphite as a support [45]. Similarly, the use of higher input power has enabled retro-Diels-Alder reactions of anthracene derivatives to occur in 3-5 min [41]. This method is an alternative to the use of flash thermolysis. The use of graphite is a prerequisite for obtaining high temperatures in a short time. 

Chemical separation of conjugated dienes and other polyunsaturated hydrocarbons is based on the availability of tt delocalized electrons. The use of a strong dienophile (e.g. tetracyanoethylene, TCNE) will derivatize only conjugated dienes, thus separating the polyunsaturated compounds into two groups. However, such derivatization is not always reversible since a retro-Diels-Alder reaction may require a high temperature. Hence, the retrieved compounds may be the thermostable ones and not those present in the initially analysed mixture. 

Joining olefin metathesis on the very short list of exchange reactions involving carbon-carbon bonds, the Diels-Alder reaction was studied in 2005 by Lehn and colleagues [52]. As the authors note, most Diels-Alder reactions proceed only in the forward direction at room temperature, with retro Diels-Alder reactions typically requiring elevated temperatures. Careful tuning of the diene and dienophile, however, can alter this significantly. In particular, reactions of substituted fulvenes (32) with diethylcyanofumarate (33) were... 

For the synthesis of carazostatin (247), the required arylamine 708 was synthesized starting from 1-methoxycyclohexa-l, 3-diene (710) and methyl 2-decynoate (711). The key step in this route is the Diels-Alder cycloaddition of 710 and 711, followed by retro-Diels-Alder reaction with extrusion of ethylene to give 2-heptyl-6-methoxybenzoate (712). Using a three-step sequence, the methoxy-carbonyl group of compound 712 was transformed to the methyl group present in the natural product. 3-Heptyl-3-methylanisole (713) was obtained in 85% overall yield. Finally, the anisole 713 was transformed to the arylamine 708 by nitration and subsequent catalytic hydrogenation. This simple sequence provides the arylamine 708 in six steps and with 26% overall yield (597,598) (Scheme 5.66). 

By using a sequence involving regio and diastereoselective reduction of the adducts (it only affects the carbonyl far away from the sulfinyl group, yielding y-oxygenated lactones), stereoselective AT-acyliminium addition, and retro Diels-Alder reactions as the main key steps, Koizumi et al. have synthesized chirally functionalized pyrrolidines [96, 97], pyrrolizidines [98], and indolizidines [98-100], depicted in Scheme 56. The milder conditions required for the evolution of the adducts derived from furan preserve the chirality of the substrates. 

Scheme 5.3. A revised synthesis of polyacetylene by the Durham route. When 2 is included in the polymer, the conversion to polyacetylene first requires that the diene be generated at 80 °C) before the retro-Diels-Alder reaction...

Retro-Diels-Alder reactions often require drastic conditions, high temperature and sometimes even flash-vacuum thermolysis (FVT). Such thermolytic procedures have been used to prepare unsaturated amino alcohols from a variety of amino alcohols. Several reactions were performed for a variety of neat liquid adducts and submitted to MW irradiation or to classical heating at the same temperature. The improvements obtained by coupling MW and the solvent-free technique are remarkable if we consider that both classical thermolysis and FVT (leading to decomposition) are poorly productive (Scheme 31). 

When triethyl l,3,5-triazine-2,4,6-tricarboxylate is treated with acetimidamide hydrochloride7 or propionimidamide hydrochloride8,9 in dimethylformamide at 90-100°C the corresponding pyrimidines are formed in 80-85% yield. The reaction proceeds by reversible in-situ tautomerism of the amidine hydrochloride to the alkene-1,1-diamine and its participation in a [4 + 2] cycloaddition with the triazine. The cycloaddition is followed by a retro Diels-Alder reaction with loss of ammonia and ethyl cyanoformate. The thermal conditions (>80°C) required for effecting the retro-Diels-Alder reaction and the deliberate use of the amidine hydrochlorides facilitates the amidine tautomerism and seems to be essential for aromatization of the initially formed cycloadduct.7-9... 

The intramolecular Diels-Alder reactions of simple, 4-hydroxy- or 4-alkyl-6-oxopyrimidines80,81 bearing olefinic, acetylenic, or nitrile dienophiles have been investigated (Table 10-VI). In many instances, the initial intramolecular pyrimidine Diels-Alder products are thermally stable due to the formation of a bicyclic amide. The elimination of cyanic acid (HNCO) apparently requires thermal tautomerization of the amide to the hydroxyimine and subsequent retro-Diels-Alder reaction. The application of these observations in the total synthesis of ( )-acetinidine has been detailed [Eqs. (20) and (21).82... 

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... 

Cyclopentadiene is a popular moiety to release in a retro Diels-Alder reaction, as the cyclohexene portion of the bicyclo[2.2.1]heptene is locked in a boat conformation, as required in the transition state for the retro (and indeed forward Diels-Alder) reaction. Other bridged bicyclic systems are also more prone to undergo retro Diels-Alder reaction. The bridged adduct from fiiran and maleic anhydride readily undergoes the retro reaction and, although the endo isomer is formed at a much faster rate, the reversible nature of the reaction leads to the accumulation of the more stable exo isomer. 

Mai and co-workers later published an improved s3mthesis of methoxsalen. Anionic [4 + 2]-cycloaddition followed by a retro-Diels-Alder reaction and esterification formed the key tricyclic intermediate in low yield. Two additional steps were required to reach the target compound. 

Intramolecular reactions provided the best examples for requiring the proper conformation for a successful Alder-Ene reaction to occur. Oftentimes, a chiral template has been used to induce chirality into the Alder-Ene reaction. Retro-Diels-Alder reaction formed 71, which revealed the enophile, followed by cyclization to 72. Notably, reactions with the E-alkenes were very slow and poor yielding, while the Z-alkenes which underwent reaction via the exo-TS led to product the -alkene required the endo-TS. The authors suggested that due to the highly strained endo-TS, the Z-alkenes reacted more smoothly. ... 

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