Diels/Alder cycloaddition

The prominence of the Diels-Alder reaction of quino-2,3-dimethanes (also known as ortfto-quinodimelhanes and rt/j( -xylylenes) has been established for nearly six decades since the seminal work by Cava [1,2], Several excellent reviews are available [3-7]. The logical extension of this chemistry to the synthesis and Diels-Alder reactions of indole-2,3-quinodimethanes (2,3-dimethylene-2,3-dihy-dro-l/7-indoles) has been recognized as an efficient route to indoles, carbazoles, and related fused indoles [8], 

Indole Ring Synthesis From Natural Products to Drug Discovery, First Edition. Gordon W. Gribble. 2016 John Wiley Sons, Ltd. Published 2016 by John Wiley Sons, Ltd. 

Following the pioneering work of Plieninger, Bergman, Moody, Marinelli, Narasimhan, Magnus, Pindur, Nandin de Carvalho, and Dmitrienko, the spark was lit for the invention of new ways to generate (even isolate ) indole-2,3-quinodimethanes. For unsuccessful attempts to isolate IQDs, see Rinderspacher [56]. 

Ar= Ph, 4-MePh, 4CI-Ph, 4-BrPh, 4-CNPh, 3-N02Ph, 2-N02Ph, 2-pyridyl, 1-naphthyl, others 

In addition to the pyrano[3,4- i]indol-3-one ring system, another group of stable indole-2,3-quinodimethane synthetic equivalents are the fused indole ring systems, pyrrolo[3,4-fc]indole, furo[3,4- ]indole, thieno[3,4- ] indole, and seleno[3,4- ]indole, each of which is known. 

There has been a vast amount of work directed towards making the Diels-Alder cycloaddition an enantioselective process, so only a small selection of the more modem methods will be shown hereJ l The most popular location for the chiral auxiliary is on the dienophile, which is generally an acrylate ester of an optically active alcohol. The idea throughout is to favour addition of the diene to the Re or Si face of the acrylate by the steric blockade of the opposite face. One of the best acrylate auxiliaries is (-)-8-phenylmenthol, introduced by Corey.1 1 The Re face is blocked here by the phenylisopropyl group leading to the formation of (115) as the major product. 

Almost invariably these cycloadditions are performed with Lewis acid catalysis. There are two main reasons for this firstly, the reaction proceeds at low temperatures, increasing the facial selectivity and for cyclic dienes, the endo preference secondly, the Lewis acid- 

Many of the chiral auxiliaries described earlier serve excellently in asymmetric Diels-Alder reactions. The Evans oxazolidinones (116)t l and the Oppolzer camphor sultams (117)t l are exceptionally good in this regard and, as shown, actually give opposite products. 

Naturally, the diastereoselective cycloaddition may be made intramolecular as illustrated by the reaction of In this case 

Asymmetric Diels-Alder reactions with dienes bearing chiral auxiliaries have been studied less extensively. One example exploits some interesting cycloreversion chemistry. [52] The source of asymmetry for diene (120) is (5)-mandelic acid. 

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In contrast to oxazole, thiazole does not undergo the Diels-Alder cycloaddition reaction (331). This behavior can be correlated with the more dienic character of oxazole, relative to thiazole, as shown by quantochemical calculations (184). 

The Diels-Alder cycloaddition is one example of a pencyclic reaction, which is a one step reaction that proceeds through a cyclic transition state Bond formation occurs at both ends of the diene system and the Diels-Alder transition state involves a cyclic array of six carbons and six tt electrons The diene must adopt the s cis conformation m the transition state... 

The product of a Diels-Alder cycloaddition always contains one more ring than was present m the reactants The dienophile maleic anhydride contains one ring so the product of Its addition to a diene contains two... 

Let us now examine the Diels-Alder cycloaddition from a molecular orbital perspective Chemical experience such as the observation that the substituents that increase the reac tivity of a dienophile tend to be those that attract electrons suggests that electrons flow from the diene to the dienophile during the reaction Thus the orbitals to be considered are the HOMO of the diene and the LUMO of the dienophile As shown m Figure 10 11 for the case of ethylene and 1 3 butadiene the symmetry properties of the HOMO of the diene and the LUMO of the dienophile permit bond formation between the ends of the diene system and the two carbons of the dienophile double bond because the necessary orbitals overlap m phase with each other Cycloaddition of a diene and an alkene is said to be a symmetry allowed reaction... 

Its Strained triple bond makes benzyne a relatively good dienophile and when benzyne IS generated in the presence of a conjugated diene Diels-Alder cycloaddition occurs... 

The transition state for the first step of the Claisen rearrangement bears much m common with the transition state for the Diels-Alder cycloaddition Both involve a con certed six electron reorganization... 

Miscellaneous Reactions. Some hydantoin derivatives can serve as precursors of carbonium—immonium electrophiles (57). 5-Alkoxyhydantoins are useful precursors of dienophiles (17), which undergo Diels-Alder cycloadditions under thermal conditions or in the presence of acid catalysis (58). The pyridine ring of Streptonigrine has been constmcted on the basis of this reaction (59). 

Polyimides have been synthesized by Diels-Alder cycloaddition of bismaleimides and substituted biscydopentadienones (81,82). The iatermediate tricychc ketone stmcture spontaneously expeU carbon monoxide to form dihydrophthalimide rings, which are readily oxidized to imides ia the presence of nitrobenzene. 

The diene undergoes Diels-Alder cycloaddition with dienophiles. Polyimides have been synthesized from various imide-containing benzocyclobutenes and dienophiles (83—85). 

The synthesis of natural products containing the quinonoid stmcture has led to intensive and extensive study of the classic diene synthesis (77). The Diels-Alder cycloaddition of quinonoid dienophiles has been reported for a wide range of dienes (78—80). Reaction of (2) with cyclopentadiene yields (79) [1200-89-1] and (80) [5439-22-5]. The analogous 1,3-cyclohexadiene adducts have been the subject of C-nmr and x-ray studies, which indicate the endo—anti—endo stereostmcture (81). 

Reaction of the azocine (212 R = Me) with DMAD yields the fused 1-azetine (213) by Diels-Alder cycloaddition to the bicyclic valence tautomer (211 R = Me) (71JOC435, 71JA152). 

Diels-Alder cycloaddition reactions, 2, 350 tautomerism, 2, 27, 152, 347 Isoquinoline, 4-hydroxy-alkylation, 2, 349 sulfonation, 2, 321... 

Recall from Section 7.13 that a stereospecific reaction is one in which each stereoisomer of a particular starting material yields a different stereoisomeric form of the reaction product. In the examples shown, the product from Diels-Alder cycloaddition of 1,3-butadiene to c/s-cinnamic acid is a stereoisomer of the product from trans-cinnamic acid. Each product, although chiral, is formed as a racemic mixture. 

An alternative approach to thionitrosoarenes involves the reaction of amines with SCla. This method has also been adapted to the production of selenonitrosoarenes ArN=Se by using the selenium(If) synthon PhSOaSeCl as the Se source (Scheme 10.2). It is likely that SeCla, generated in situ in THF, could also be used in this process. The Diels-Alder cycloaddition of ArN=Se species with dimethylbutadiene gives 1,2-selenazine derivatives in low yields. 

As it happens, the frontier orbital interactions in the Diels-Alder cycloaddition shown above are like those found in the middle drawing, i.e., the upper and lower interactions reinforce and the reaction proceeds. The cycloaddition of two ethene molecules (shown below), however, involves a frontier orbital interaction like the one on the right, so this reaction does not occur. 

Both of the reactions, radical combination and Diels-Alder cycloaddition, cause new bonds to be made. Bond making normally releases energy. Why then are the barriers for the two reactions so different (Hint Consider the nel bond making/bond breaking in the two reactions.)... 

LUMO energies for free and complexed acrylonitrile are. 103 and. 089 au (65 and 56 kcal/mol), respectively. On the basis of orbital energies, would you expect BF3 to enhance, retard, or leave unchanged the rate of Diels-Alder cycloaddition ... 

UV irradiation. Indeed, thermal reaction of 1-phenyl-3,4-dimethylphosphole with (C5HloNH)Mo(CO)4 leads to 155 (M = Mo) and not to 154 (M = Mo, R = Ph). Complex 155 (M = Mo) converts into 154 (M = Mo, R = Ph) under UV irradiation. This route was confirmed by a photochemical reaction between 3,4-dimethyl-l-phenylphosphole and Mo(CO)6 when both 146 (M = Mo, R = Ph, R = R = H, R = R" = Me) and 155 (M = Mo) resulted (89IC4536). In excess phosphole, the product was 156. A similar chromium complex is known [82JCS(CC)667]. Complex 146 (M = Mo, R = Ph, r2 = R = H, R = R = Me) enters [4 -H 2] Diels-Alder cycloaddition with diphenylvinylphosphine to give 157. However, from the viewpoint of Woodward-Hoffmann rules and on the basis of the study of UV irradiation of 1,2,5-trimethylphosphole, it is highly probable that [2 - - 2] dimers are the initial products of dimerization, and [4 - - 2] dimers are the final results of thermally allowed intramolecular rearrangement of [2 - - 2] dimers. This hypothesis was confirmed by the data obtained from the reaction of 1-phenylphosphole with molybdenum hexacarbonyl under UV irradiation the head-to-tail structure of the complex 158. 

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