Diels retro-cycloaddition

Intramolecular cycloadditions are among the most efficient methods for the synthesis of fused bicyclic ring systems [30]. From this perspective, the hetisine skeleton encompasses two key retro-cycloaddition key elements. (1) a bridging pyrrolidine ring accessible via a [3+2] azomethine dipolar cycloaddition and (2) a [2.2.2] bicyclo-octane accessible via a [4+2] Diels-Alder carbocyclic cycloaddition (Chart 1.4). While intramolecular [4+2] Diels—Alder cycloadditions to form [2.2.2] bicycle-octane systems have extensive precedence [3+2], azomethine dipolar cycloadditions to form highly fused aza systems are rare [31-33]. The staging of these two operations in sequence is critical to a unified synthetic plan. As the proposed [3+2] dipolar cycloaddition is expected to be the more challenging of the two transformations, it should be conducted in an early phase in the forward synthetic direction. As a result, a retrosynthetic analysis would entail initial consideration of the [4+2] cycloaddition to arrive at the optimal retrosynthetic C-C bond disconnections for this transformation. 

Microwave heating has also been employed for performing retro-Diels-Alder cycloaddition reactions, as exemplified in Scheme 6.94. In the context of preparing optically pure cross-conjugated cydopentadienones as precursors to arachidonic acid derivatives, Evans, Eddolls, and coworkers performed microwave-mediated Lewis acid-catalyzed retro-Diels-Alder reactions of suitable exo-cyclic enone building blocks [193, 194], The microwave-mediated transformations were performed in dichloromethane at 60-100 °C with 0.5 equivalents of methylaluminum dichloride as catalyst and 5 equivalents of maleic anhydride as cyclopentadiene trap. In most cases, the reaction was stopped after 30 min since continued irradiation eroded the product yields. The use of short bursts of microwave irradiation minimized doublebond isomerization. 

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). 

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). 

Reaction of an -substituted pyrrole with an alkynic dienophile provides access to a 3,4-disubstituted pyrrole through a Diels-Alder/retro-Diels-Alder cycloaddition process (73CJC1089). The 3,4-pyrroledicarboxylic ester (206) prepared in this way has been converted to the antimitotic agent Verrucarin E (207 Scheme 44). 

Diels-Alder reactions like the one illustrated opposite are cycloadditions mobilising six electrons. The dimerization of cyclopentadiene 1.1 is another Diels-Alder reaction, but also illustrates its inherent reversibility—cracking the dimer 1.2 on heating is called a retro-cycloaddition or a cycloreversion. 

The cyclopent-2-enone required for the photodimerisation is prepared by the hydrolysis and oxidation of 3-chlorocyclopentene, which is obtained by the low temperature addition of hydrogen chloride to cyclopentadiene. The latter is obtained by heating dicyclopentadiene. This depolymerisation is an example of a reverse (or retro) Diels-Alder cycloaddition reaction the diene readily reforms the dicyclopentadiene on standing at room temperature. 

Scheme3.2. Fragmentation via retro-Diels-Alder cycloaddition and retro-aldol addition.

Annulated pyridines are reported to be synthesized via a [4+2] cycloaddition involving oxazoles (Scheme 121 Table 10) <20010L877>. The reaction mechanism is classified as a domino process with an intramolecular Diels-Alder cycloaddition followed by a retro-Michael reaction. 

Fig. 9a4) between cyclopentadiene and a C=C bond of the dumbbell-shaped part of the rotaxane. The dumbbell-shaped part contains two dicarbonyl stations (Fig. 9a3), one derived from fumaric acid (tram -CO-C H=CH-CO-. station 1), the other derived from succinic acid (—CO-CH2-CH2-CO-, station 2). The two diamide sites of the macrocycle can form four H-bonds with the two carbonyl groups of a given station (Fig. 9al for the interaction of the two carbonyl groups of fumaric-acid-derived station 1 with the four NH groups of the macrocycle through four H-bonds, see Fig. 9a2). Station 1 (derived from fumaric acid) has a tram C=C double bond due to its preorganization, this station interacts with the macrocycle better than the station 2. Consequently, the macrocycle is initially located at station 1 (Fig. 9a5). The Diels-Alder cycloaddition (80° C, 90% yield) of cyclopentadiene to the double bond of station 1 results in a mixture of diastereomers (Fig. 9a4) and causes displacement of the macrocycle from station 1 to station 2 (Fig. 9a6). The cycloaddition is reversible and the retro-Diels-Alder reaction occurs quantitatively (250°C, reduced pressure) when cyclopentadiene dissociates from the axle of the rotaxane this produces a displacement of the macrocycle from station 2 back to station 1. 

The Stereoselectivity of Diels-Alder Reactions. One of the most challenging stereochemical findings is Alder s endo rule for Diels-Alder reactions. The favoured transition structure 6.180 has the electron-withdrawing substituents in the more hindered environment, under the diene unit, giving the kinetically more favourable but thermodynamically less favourable adduct 6.181. Heating eventually equilibrates the adducts in favour of the exo adduct 6.182, by a retro-cycloaddition re-addition pathway. 

Further examples of Diels-Alder cycloaddition reactions with small or negligible rate solvent effects can be found in the literature [531-535], The thermolysis of 7-oxabicyclo[2.2.1]hept-5-ene derivatives is an example of a solvent-independent retro-Diels-Alder reaction [537]. For some theoretical treatments of the solvent influence on Diels-Alder cycloaddition reactions, which, in general, confirm their small solvent-dependence, see references [536, 797-799]. 

Retro-Diels-Alder cycloaddition Retro-Michael addition Retro [2 + 2] cycloaddition... 

When cyclic product, the reaction is called a cycloaddition. The reverse reaction is called a retro-cycloaddition. Cycloadditions are further classified as [m + n] according to the number of atoms in each component. Again, it is important to note not only the number of atoms but also the number of electrons involved in the process. You are already familiar with the six-electron [4 + 2] cycloaddition, the Diels Alder reaction. Four-electron [2 + 2] cycloadditions are less common, for reasons that will be discussed, but ketenes undergo them readily. The [3 + 2] cycloadditions (or 1,3-dipolar cycloadditions) are a very important class of six-electron cycloadditions that are used to make a wide variety of five-membered heterocycles. Other cycloadditions, including [8 + 2], [4 + 3], and [6 + 4] cycloadditions, are also known. 

There are other kinds of cycloadditions, too. The [4 + 1] cycloaddition, a cheletropic reaction, usually goes in the retro direction for entropic reasons. 3-Sulfolene (butadiene sulfone, 2,5-dihydrothiophene 1,1-dioxide) undergoes a [4 + 1] retro-cycloaddition to generate S02 and 1,3-butadiene, which can undergo a Diels-Alder reaction with a dienophile. It is much more convenient to... 

Cyclopentadienones are very prone to do Diels-Alder reactions because of their enforced s-cis conformation and their antiaromaticity. The Diels-Alder reaction of a substituted cyclopentadienone and an alkyne is followed immediately by a [4 + 1] retro-cycloaddition to generate CO and an aromatic compound. 

The end of the catalytic cycle can be drawn differently. The cobaltacyclopentadiene is particularly well arranged to undergo a Diels-Alder reaction with another equivalent of PhC=CPh. A [4 + 1] retro-cycloaddition then gives the product C6Ph6 and regenerates the catalyst CpCo(I). 

Cycloadditions are characterised by two components coming together to form two new a bonds, one at each end of both components, joining them together to form a ring, with a reduction in the length of the conjugated system of orbitals in each component (Fig. 6.1a). Cycloadditions like the Diels-Alder reaction are by far the most abundant, varied, featureful and useful of all pericyclic reactions. They are inherently reversible, and the reverse reaction is called a retro-cycloaddition or a cycloreversion. 

In a study described by Kappe et al. (Section 11.4.1) [58], the intermolecular Diels-Alder cycloaddition reaction of the pyrazinone heterodiene 52 with ethylene led to the bicyclic cycloadduct S3 (Scheme 11.15). Under conventional conditions these cycloaddition reactions must be conducted in an autoclave at an ethylene pressure of 25 bar at 110 °C for 12 h. In contrast, under the action of microwaves, he Diels-Alder addition of pyrazinone precursor 52 to ethylene in a sealed vessel flushed with ethylene before sealing was complete after 140 min at 190 °C. It was not, however, possible to further increase the reaction rate by increasing the temperature. At temperatures above 200 °C an equilibrium between the cycloaddition 52 S3 and the competing retro Diels-Alder fragmentation process was observed (Scheme 11.15) [58]. By use of a microwave reactor enabling pre-pressurization of the reaction vessel with 10 bar ethylene, however, the Diels-Alder addition 52 S3 was definitely more efficient at 190 °C 85% yield of adduct 53 was obtained within 20 min [65b]. 

Thioketones of various types are readily available and are well documented as effective dienophiles. Representative thioketone cycloadditions are listed in Table 5-1. In general, it appears that thioketones usually add to most dienes in high yield at exceptionally low temperatures to afford stable adducts, although some of these adducts tend to undergo retro-Diels-Alder reactions. - Very little has been done toward establishing the regiochemical selectivity of thioketone additions to unsymmetrical 1,3-dienes, and the few such entries in Table 5-1 indicate that mixtures were obtained. The exo/endo stereochemistry of [4 + 2] cycloadditions with unsymmetrical thioketones has not been probed to date. It has been reported that Diels-Alder cycloadditions of thioketones can also be pho-tochemically induced. 

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