Diels-Alder cycloadditions, double

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... 

Dienophile (Section 14.5) A compound containing a double bond that can take part in the Diels-Alder cycloaddition reaction. The most reactive dienophiles are those that have electron-withdrawing groups on the double bond. 

Anionic Diels-Alder reactions have been studied less extensively with the interest having been focused mainly on the cycloaddition of enolates of a,/l-unsaturated ketones with electron-poor olefins [24] (Equations 1.8 and 1.9). These reactions are fast and stereoselective and can be regarded as a sequential double Michael condensation, but a mechanism involving a Diels-Alder cycloaddition seems to be preferred [24b,f, 25]. 

The non-preservation of cis stereochemistry of dienophiles 24 and 26 in the adducts 25 and 27 is due to a cis-trans photoisomerization of the double bond and to the concerted suprafacial Diels-Alder cycloaddition of diene to the ground state of trans dienophiles. 

Double Diels-Alder cycloadditions of 2-(1H)-pyridones acting as dienophiles [92]... 

Perhaps the most characteristic property of the carbon-carbon double bond is its ability readily to undergo addition reactions with a wide range of reagent types. It will be useful to consider addition reactions in terms of several categories (a) electrophilic additions (b) nucleophilic additions (c) radical additions (d) carbene additions (e) Diels-Alder cycloadditions and (f) 1,3-dipolar additions. 

MCP (1) is not known to undergo [4 + 2] cycloadditions. The substitution of two, or more, ring protons with fluorine atoms, however, seems to improve dramatically the dienophilic reactivity of the exocyclic double bond. 2,2-Di-fluoromethylenecyclopropane (5) is a quite reactive dienophile in Diels-Alder cycloadditions. With cyclopentadiene (6) and furan (7), it formed two isomeric adducts (Scheme 1) [9]. In both cases the adduct with the endo CF2 group is the major isomer. 

Diarylmethylenecyclopropa[6]naphthalenes 14, unlike their benzene parent counterparts which give cycloaddition reactions at the cyclopropene bridge bond [10a], react on the exo double bond in Diels-Alder cycloadditions (see Sect. 2.1.1) [10b]. The reactions of 14 with the highly electron-deficient acetylenic(phenyl)iodonium triflate 584 give products 586a and 587, which are believed to derive from unstable primary [2 + 2] cycloadducts 585 (Scheme 82) [10b],... 

A similar transformation occurs as a critical step in the total synthesis of (+)-estrone by a Diels-Alder cycloaddition-cycloreversion pathway (Eq. 80).227 It is worth noting that in this reaction the conjugated double bond is stereoselectively reduced while both an isolated double bond and a ketone carbonyl are preserved. 

An electron-withdrawing group on the alkenyl double bond has been shown to greatly facilitate the Diels-Alder cycloaddition with furan as depicted below < 00TL9387>. 

Another example, in which the piperidine cycle is generated de novo, exploits a hetero Diels-Alder cycloaddition of 1 -/r-tolylsulfinyl-1,3-penta-diene 91 with benzylnitrosoformate, that generates an oxazine 92 with complete regioselectivity and 7i-facial diastereoselectivity.69 Osmilation of the double bond inserts stereoselectively two hydroxyl groups on the oxazine skeleton, protection and catalytic hydrogenation finally afforded the enantiomerically pure imino sugars 94 (Fig. 38). 

Details of various routes to allylphosphine oxides (43) have been reported, and the subsequent synthesis of 1,3-dienes has been illustrated by many examples.37 Also described are stereochemical aspects of these diene syntheses and of subsequent Diels-Alder cycloaddition reactions.37 High regioselectivity is observed in migrations of the diphenylphosphinoyl group from unsymmetrical sites, as in (44), in that both products have a double bond exocydic to the cyclohexane ring.38... 

An example of the second type of modification is the application of the Diels-Alder cycloaddition reaction to polders and copol ers containing pendant or backbone furan moieties. The use of bis-dienophiles such as propiolic acid and its esters or bis-maleimides provides a means of crosslinking based on multiple bridging by the double interchain lycloadditions. The thermal reversibility of these reactions allows the return to the original linear structure (thermoplastic material) by simply heating the gel. 

Wittig olefination of 2-nitro-Z-cinnamaldehyde (1300) with the phosphonium bromide 1301 led to the diene 1302. The Diels-Alder cycloaddition of 1302 with maleimide (1303), followed by dehydrogenation with DDQ, afforded the phthali-mide 1304. Double deoxygenation of 1304 with triphenylphosphine (PPhs) in collidine gave O-methylarcyiiaflavin B (1305). Finally, heating of 1305 with molten pyridine hydrochloride led to arcyriaflavin B (346) (759) (Scheme 5.215). 

The pyrone ring then acts as the dienophile in the intramolecular Diels-Alder cycloaddition, which was conducted in a microwave oven. The final step of this synthesis is a high-temperature ester pyrolysis to introduce the exocyclic double bond of longifolene. 

The aprotic double Michael addition was discovered by R. A. Lee and to synthesize functionalized bicyclo[2.2.2]octanes which may serve as starting materials in natural products syntheses (Table I). These ljicyclo[2,2.2]octanes can also be obtained by a Diels-Alder cycloaddition of 2-trimethyl5iloxy-substituted cyclohexadienes and dienophiles H... 

An approach to the synthesis of angularly substituted polycyclics through the Diels-Alder cycloaddition of dihydrothiophenes has been devised (69JA7780). The easily prepared 2,5-dihydro-4-methoxycarbonyl-2-thiopheneacetic acid methyl ester (316) was heated at 180 °C with excess butadiene to yield (317). Desulfurization and double bond reduction of the cycloadduct with W-5 Raney nickel gave (318) which was characterized by conversion to the corresponding diacid and comparison with an authentic sample. Dieckmann cyclization of (318) is known to lead to the 5-methyl-1-hydrindanone (319 Scheme 68). The use of other dienes in the [4 + 2] cycloaddition process will, of course, produce more highly functionalized hydrindanones. 

Scheme 34 shows the synthesis of the bc portion (336), which possessed three of the nine asymmetric centers present in cobyric acid. Retrosynthesis determined that (336) could be obtained, via sulfide contraction, from the two intermediates (337) and (338). Ring c was synthesized from (+)-camphor quinone (not shown). Ring b (337) was obtained from 8-methyl-j8-acetylacrylic acid (339), the two adjacent chiral centers being generated in the required relative orientation by a Diels-Alder cycloaddition with butadiene in the presence of tin(IV) chloride. Fractional crystallization served to resolve the diastereomeric a-phenethylamine salts derived from them, eventually affording the compound (340). Oxidation with chromic acid cleaved the double bond in (340) and one of the newly generated... 

The mechanistically quite similar double Michael reaction of 2-silyloxy dienes and enones has been shown recently to go via a similar two-step mechanism rather than a Diels-Alder cycloaddition S. Kobayashi, Y. Sagawa, H. Akamatsu and T. Mukaiyama, Chem. Lett., 1988, 1777. 

Scheme 22)87 The intramolecular 4 + 2-cycloaddition of ynamides with conjugated enynes produces substituted indolines that can be oxidized to indoles with o-chloranil.88 The double Diels-Alder cycloaddition of the linear conjugated tetraene... 

In order to confirm the stmcture of the tricyclic thietane 60, it underwent several reactions <20040L1313>, which were performed on the substituent of the ring carbon atom. The thietane 60 underwent hydrogenation on palladium-on-charcoal to give the fully saturated compound 61. The presence of a double bond in compound 60 was also confirmed by [4+2] Diels-Alder cycloaddition of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate as well as of diphenyl-isobenzofuran, which led to the formation of cycloadducts 62 and 63, respectively (Scheme 10) <20040L1313>. 

The double bond of maleimides in very reactive towards electron-rich dienes, to give a normal Diels-Alder cycloaddition. Thus BMIs were used to obtain linear polyimides by reaction with several kind of dienes [46-51]. However the dienes are often difficult to prepare [51] and functionalized dienes have been used. Furan terminated oligomers react with BMIs at 70 °C leading to an oxygen-containing cycloadduct [52-57] which can react with acetic anhydride to give an aromatic imide (Fig. 13) [58-59]. 

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