Intermolecular Diels-Alder cycloadditions

Asymmetric induction in the intermolecular Diels-Alder cycloaddition reactions can be achieved with chirally modified dienes and dienophiles as well as with chiral Lewis-acid catalysts [54-56]. 

The readily available enantiopure acyclic hydroxy 2-sulfinyl butadiene 585 undergoes a highly face-selective Diels-Alder cycloaddition with PTAD to generate the densely functionalized cycloadduct 586 (Equation 84). The complete reversal of facial selectivity is observed when sulfonyl derivative 587 is treated with PTAD under identical conditions (Equation 85). These results demonstrate that the sulfinyl functionality is not just synthetically useful but also an extremely powerful element of stereocontrol for intermolecular Diels-Alder cycloadditions. On the other hand, the corresponding ( , )-hydroxy-2-sulfinyldienes treated with PTAD affords the cycloadducts in high yield but with moderate 7i-facial selectivity <1998CC409, 2005CEJ5136>. 

Since their original discovery [362] pericyclic radical cation reactions have been developed for various synthetic formats. The methodology nowadays is most advanced for intra- [363] and intermolecular Diels-Alder cycloadditions [364], and... 

The critical step in the enantioselective and stereocontrolled total synthesis of eunicenone A by E.J. Corey et al. was the highly efficient chiral Lewis acid catalyzed intermolecular Diels-Alder cycloaddition reaction The diene component was mixed with 5 equivalents of 2-bromoacrolein and 0.5 equivalents of the chiral oxazaborolidine catalyst in CH2CI2 at -78 °C for 48h. The reaction gave 80% of the desired cycloadduct in 97% ee and the endolexo selectivity was 98 2. 

Certain functional groups can direct through hydrogen-bonding the outcome of the intermolecular Diels-Alder cycloaddition. This was the case in the key Diels-Alder cycloaddition step during the total synthesis of ( )-rishirilide B in the laboratory of S.J. Danishefsky. The diene was thermally generated in situ. 

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]. 

Explain why intermolecular Diels-Alder cycloaddition reactions usually fail with unactivated dienophiles such as ethene. 

Intermolecular Diels-Alder cycloaddition reactions usually fail with unactivated dienophiles as the energy of the LUMO of such dienophiles is normally high and therefore the interaction of this molecular orbital with that of the HOMO of the diene is poor (orbitals of similar energy interact more strongly). Filled-unfilled orbital interactions are crucial for successful Diels-Alder reactions, which are typically frontier-orbital controlled. See Section 3.1.1. 

Scheme 4.14 Gold catalyzed synthesis of azepines via an intermolecular Diels-Alder cycloaddition.

Scheme 97 [4+2] intermolecular Diels-Alder cycloaddition followed by intramolecular [4+2] cycloaddition of 3,4-dichloro-, tetrabromo-, and tetrachlorothiophene 1,1 -dioxides with cyclic and acyclic non-conjugated dienes [103]... 

The Diels-Alder cycloaddition is the best-known organic reaction that is widely used to construct, in a regio- and stereo-controlled way, a six-membered ring with up to four stereogenic centers. With the potential of forming carbon-carbon, carbon-heteroatom and heteroatom-heteroatom bonds, the reaction is a versatile synthetic tool for constructing simple and complex molecules [1], Scheme 1.1 illustrates two examples the synthesis of a small molecule such as the tricyclic compound 1 by intermolecular Diels-Alder reaction [2] and the construction of a complex compound, like 2, which is the key intermediate in the synthesis of (-)chlorothricolide 3, by a combination of an intermolecular and an intramolecular Diels-Alder cycloaddition [3]. 

The rates of intermolecular Diels-Alder reactions of hydrophobic dienes and dienophiles are significantly increased when the cycloadditions are performed in pure ethylene glycol (EG) [49a]. Some examples are illustrated in Scheme 6.30. This performance is due to the fact that the EG (i) forms extensive hydrogen bonding, (ii) is able to solubilize hydrophobic dienes and dienophiles, and (hi) forms molecular aggregations with the reactants. 

Grieco utilized an aqueous intermolecular Diels-Alder reaction as the key step in forming the AB ring system of the potent cytotoxic sesquiterpene vernolepin. 87 Cycloaddition of sodium ( >3,5-hexa-dienoate with an a-substituted acrolein in water followed by direct reduction of the intermediate Diels-Alder adduct gave the desired product in 91% overall yield (Eq. 12.28). 

So far, only those domino Knoevenagel/hetero-Diels-Alder reactions have been discussed where the cycloaddition takes place at an intramolecular mode however, the reaction can also be performed as a three-component transformation by applying an intermolecular Diels-Alder reaction. In this process again as the first step a Knoevenagel reaction of an aldehyde or a ketone with a 1,3-dicarbonyl compound occurs. However, the second step is now an intermolecular hetero-Diels-Alder reaction of the formed 1 -oxa-1,3 -butadiene with a dienophile in the reaction mixture. The scope of this type of reaction, and especially the possibility of obtaining highly diversified molecules, is even higher than in the case of the two-component transformation. The stereoselectivity of the cycloaddition step is found to be less pronounced, however. 

The combination of two successive [4+2] cycloadditions has already been described by Diels and Alder [la] for the reaction of dimethyl acetylenedicarboxylate with an excess of furan. A beautiful, more modern, example is the synthesis of pagodane (4-5) by Prinzbach [2], in which an intermolecular Diels-Alder reaction of 4-1 and 4-2 to give 4-3 is followed by an intramolecular cycloaddition. The obtained 4-4 is then transformed into 4-5 (Scheme 4.1). 

In the intermolecular series, Diels-Alder cycloaddition of ethene to the pyrazi-none heterodiene led to the expected bicyclic cycloadduct (Scheme 6.95 b) [195], The details of this transformation, performed in pre-pressurized reaction vessels, are described in Section 4.3.2 [196], Similar cycloaddition reactions have also been studied on a solid phase (Scheme 7.58) [197]. 

In an approach by Jung and Nishimura, the assembly of the dysidiolide decalin skeleton 54 was deemed possible via an intermolecular Diels-Alder reaction between cydohexene 52 and dienophile 53 [14]. Based on precedent established by Wulff et al. [15] [where Z = C(OCH3)=Cr(CO)5], the cycloaddition should give predominantly the exo isomer as shown (Scheme 19.12). However, all attempts to effect the cydoad-dition simply gave recovery of starting material. It was reasoned that steric hindrance was to blame. The steric hindrance assodated with the dienophile was decreased by replacing one of the methyl groups with another double bond in the... 

However, when pyridyliminophosphorane (306a) is treated with phenyl isocyanate or isothiocyanate (Scheme 110), mixed carbodiimides are obtained, which are capable of an intermolecular Diels-Alder reaction resulting in triazine 308. The cycloaddition occurs specifically with one C = N double bond of the carbodiimide serving as the dienophile (77ZC371). 

Bicyclopropylidene (1) does not undergo an intermolecular Diels-Alder reaction with furan and 2-methoxyfuran even under high pressure. Intramolecular cycloadditions of compounds 160 with a furan tethered to bicyclopropylidene, however, were easily brought about under high pressure (10 kbar) and gave cycloadducts 161 stereoselectively in yields ranging from 32 to 95% (Scheme 35) [58]. 

Subsequently to the intermolecular Diels-Alder reaction, a new diene is produced which can then be utilized in a second cycloaddition process. The feasibility of the second Diels-Alder process was demonstrated by the thermal cycloaddition of 44 with a variety of dienophiles to afford the cycloadducts 47 in high yields, albeit with moderate diastereoselectivity (Scheme 8.8). Additional investigations will be necessary to delineate further the scope and limitations of this rapid increase in molecular complexity. 

As can be seen in the intramolecular cycloaddition (Section 8.03.5.1), the intermolecular Diels-Alder reactions between functionalized 2(l/f)-pyrazinones 83 and dimethyl acetylenedicarboxylate (DMAD) forming bicyclo adducts 84 has been shown to be significantly rate enhanced and increased in yields by using controlled microwave irradiation compared to the conventional thermal protocols (Scheme 21) <2002JOC7904>. The microwave-assisted Diels-Alder reactions of substituted 2(l//)-pyrazinones with ethene are significantly more effective utilizing prepressurized (up to 10 bar) reaction vessels <20040BC154>. 

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). 

There is an excellent recent review on intramolecular dipolar cycloadditions.1 Reviews on mechanistic aspects of intermolecular 1,3-dipolar cycloadditions abound2 and a treatise on intramolecular Diels-Alder cycloadditions is available.3... 

Intermolecular Diels-Alder W. Oppolzer in COS, Ch. 4.1 hetero J. Hamer, 1,4-Cycloaddition Reactions, Academic Press, New York, 1967 D. L. Boger and S. M. Weinreb, Hetero Diels-Alder Methodology in Organic Synthesis, Academic Press, New York, 1967 B Weinreb in COS, Ch. 4.2 D. 

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