Diels—Alder process

Because the fluorine substituents both inductively and hyperconjugatively withdraw electron density from the C(2)-C(3) tt bond, the LUMO is located there, and Diels-Alder reactions take place exclusively with this bond [25] 1,1 -Difluoro allene and fluoroallene reaet readily with a large selection of cyclic and acyclic dienes, and acyclic dienes, [2+2] cycloadditions compete with the Diels-Alder processes As shown in the example in equation 79, a significantly different regiochemistry is observed for the [2+4] cycloaddition compared with the [2+2]... 

A special method, with only two examples, starts from 1,2,4-triazines.20 21 Diels-Alder reaction with the strained dienophile dimethyl tricyclo[4.2.2.02,5]deca-3,7,9-triene-7,8-dicarboxylate (14) is followed by an elimination of nitrogen via a retro-Diels-Alder process. The formed product, however, cannot be isolated, but reacts via another retro-Diels-Alder reaction and an electro-cyclic reaction to provide the azocine derivative 15. The sequence order of the reactions is not clear, but both pathways lead to the same product. 

V-Acyliminium ions act as dienophiles in [4 + 2] cycloaddition reactions with conjugated dienes13, while A-acylimimum ions that (can) adopt an x-cis conformation are able to act as heterodienes in an inverse electron demand Diels-Alder process with alkenes or alkynes3 (see Section D. 1.6.1.1.). 

Cycloaddition of 125 with buckminsterfullerene (Ceo) at 3 kbar allowed the adduct [48] to be obtained, preventing a retro Diels-Alder process (Scheme 5.19). Cycloadditions of tropone (125) with furans 134 gave mixtures of 1 1 endo-dcad exo-monocycloadducts 135 and 136, respectively [49a], together with some bisadducts. In this case furan reacts solely as the 27t component in spite of its diene system. Whereas 2-methoxy furan gave mainly the kinetically controlled product 135 (R= OMe Ri =R2 =H), under the same conditions 3,4-dimethoxy furan afforded the thermodynamically controlled cycloadduct 136 (R=H Ri =R2 =OMe) as the major product (Scheme 5.19). 

Terrier et al. have widely described Bfxs 4-nitro-substituted participating in a series of Diels-Alder processes. Bfx 4-nitro-substituted system could participate as diene, C = C - C = C system, or heterodiene, C = C - NO2 system, in an inverse electron demand reaction [62,63] or as dienophile, C = C or N = O systems, in a normal electron demand reaction [64-68]. Fxs have been reported as 1,3-dipole through the substructure C = - 0 reacting with... 

To conclusively disprove the involvement of the chromanol methide radical, the reaction of a-tocopherol with dibenzoyl peroxide was conducted in the presence of a large excess of ethyl vinyl ether used as a solvent component. If 5a-a-tocopheryl benzoate (11) was formed homolytically according to Fig. 6.6, the presence of ethyl vinyl ether should have no large influence on the product distribution. However, if (11) was formed heterolytically according to Fig. 6.9, the intermediate o-QM 3 would be readily trapped by ethyl vinyl ether in a hetero-Diels-Alder process with inverse electron demand,27 thus drastically reducing the amount of 11 formed. Exactly the latter outcome was observed experimentally. In fact, using a 10-fold excess of ethyl vinyl ether relative to a-tocopherol and azobis(isobutyronitrile) (AIBN) as radical... 

The last reaction commonly evoked to support the involvement of radical species 10 in tocopherol chemistry is the disproportionation of two molecules into the phenol a-tocopherol and the ort/zo-quinone methide 3 (Fig. 6.8), the latter immediately dimerizing into spiro dimer 9. This dimerization is actually a hetero-Diels-Alder process with inverse electron demand. It is largely favored, which is also reflected by the fact that spiro dimer 9 is an almost ubiquitous product and byproduct in vitamin E chemistry.28,29 The disproportionation mechanism was proposed to account for the fact that in reactions of tocopheroxyl radical 2 generated without chemical coreactants, that is, by irradiation, the spiro dimer 9 was the only major product found. 

Scheme 1.47. Domino-1,3-rearrangement/Diels-Alder process.

Another attractive two-component domino Knoevenagel/hetero-Diels-Alder process employing the enantiopure aldehyde 2-773 and the hydroxypyridones 2-772 has been reported by the group of Snider (Scheme 2.171) [385]. The product, tricyclic compound 2-775, was obtained in 35% yield, and transformed into leporin A (2-776) [386],... 

Instead of the usual 1,3-dicarbonyl compounds, heteroanalogues such as the corresponding a-carbonylated phosphonates 2-810 can also be used in the Knoevenagel/hetero-Diels-Alder process. As in the case of carbonyl groups at the... 

The domino process probably involves the chiral enamine intermediate 2-817 formed by reaction of ketone 2-813 with 2-815. With regard to the subsequent cy-doaddition step of 2-817 with the Knoevenagel condensation product 2-816, it is interesting to note that only a normal Diels-Alder process operates with the 1,3-bu-tadiene moiety in 2-817 and not a hetero-Diels-Alder reaction with the 1-oxa-l,3-butadiene moiety in 2-816. The formed spirocydic ketones 2-818/2-819 can be used in natural products synthesis and in medidnal chemistry [410]. They have also been used in the preparation of exotic amino adds these were used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins... 

Recently, Mander and coworkers [122] reported the total synthesis of sordaricin (4-347), the aglycone of the potent antifungal diterpene sordarin which was first isolated in 1971 from the ascomycete Sordaria araneosa. Two approaches were explored the first method utilized a possible biogenetic Diels-Alder reaction the second was based on a domino retro-Diels-Alder/intramolecular Diels-Alder process. Thus, heating of 4-348 led, with extrusion of cyclopentadiene, to a 1,3-butadiene as intermediate which underwent an intramolecular Diels-Alder reaction to give the desired 4-349 as the main product, together with a small amount of 4-350 (Scheme 4.77). 

Another photoinduced 1,5-hydrogen shift/twofold Diels-Alder process to give substituted aromatic compounds has been reported by Nair and coworkers [34]. 

Another domino Heck/Diels-Alder process described by the same group [64] implies the Pd°-catalyzed reaction of 6/1-118 in the presence of acrylate or methyl vinyl ketone to give the corresponding bicyclic compounds 6/1-120 and 6/1-121 via the transient 6/1-119 (Scheme 6/1.32). Good yields were obtained only if potassium carbonate is used as base. 

Scheme 10.11. Domino Ugi/Diels-Alder process on a MPEG-0-CH2-platform.

Recently, Oikawa and coworkers also published a successful parallel synthesis using a domino Ugi/Diels-Alder process [14]. Thus, reaction of immobilized fur-... 

In order to study any chemoselectivity influences of microwave irradiation on the domino Knoevenagel/hetero-Diels-Alder process (the so-called Tietze reaction), Raghunathan and coworkers [31a] investigated the transformation of 4-hydroxy coumarins (10-85) with benzaldehydes 10-86 in EtOH to afford pyrano[2,3-c]cou-marin 10-87 and pyrano[2,3-b]chromone derivatives 10-88. Normal heating of 10-85a and 10-86a at reflux for 4h gave a 68 32 mixture of 10-87a and 10-88 in 57% yield, whereas under microwave irradiation a 97 7 mixture in 82% yield was obtained. Similar results were found using the benzo-annulated substrates 10-85b and 10-86b. 

Under the conditions of the cobalt-mediated carbonylative A-oxide-promoted cocyclization (Pauson-Khand reaction) at room temperature, compound 547 provides exocyclic 1,3-diene 548 as the major product (>98%) together with only traces of the corresponding carbonylative product 549. Owing to the relative instability of the diene, it is more efficient to perform a one-pot cobalt cyclization/Diels-Alder process after A-oxide-promoted cyclization of the cobalt complexes. Compound 550 is obtained as a single diastereomer in 39% overall yield if MTAD is used as a dienophile (Scheme 90) <2003JOC2975>. 

There are few transformations that can, in a single stroke, provide the structural and stereochemical complexities that are attained through a Diels-Alder cydoaddition. It is little surprise then that numerous studies have appeared in the past decade that aim to develop a catalytic asymmetric Diels-Alder process. It is only in a few instances, however, that these catalytic asymmetric protocols have been applied to target-oriented synthesis. Several impres-... 

The presence of one or more heteroatoms in either the 4jt or In component allows the synthesis of six-memebered heterocycles via the Diels-Alder process. These strategies have been successfully developed (218) leading to a diverse array of natural products. Similar to the carbo-Diels-Alder reaction, many of these processes are amenable to Lewis acid acceleration, and several have been developed using chiral catalysts. 

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. 

While most other techniques failed, MS was quite successful in distinguishing between the two isomers (20) and (21) (Scheme 5). While the 7-one (20) undergoes a retro Diels-Alder process and exhibits a diagnostic fragmentation pattern at m/z 203 and 102, these peaks are lacking in (21)... 

JHC297>. In a continuation of the above work, l,3,4-thiadiazolo[3,2-a][l,3,5]-triazines were also analyzed by electron impact mass spectrometry. A retro Diels-Alder process gave two fragments (Equation (1)) which in turn were further fragmented into smaller molecules. The mass spectral data for the 11 compounds analyzed has been tabulated in great detail <890MS(24)379>. 

Fused pyridazines, such as 3, that have a chloro substituent a to the nitrogen in the pyridazine ring react with electron-rich ynamines in a reaction sequence including an inverse electron demand Diels-Alder process to give the corresponding pentasubstituted pyridines (Equation 2) <1994CPB2219>. Another isomer of the pyrrolopyridazine as well as a furopyridazine behaved similarly <1994CPB2219>. 

A 4-ethoxycarbonylpyrimidine-2-thione can serve as the dienophile component in which the pyrimido[4,5-rflpyrimi-dine system is formed by a hetero-Diels-Alder process (Equation 94) PM3 calculations predict a preference for the endo rather than the o-pathway, and in practice the OTr/o-adduct is the sole product <2005T4237>. 

Aqueous hetero Diels-Alder reaction was first described by Grieco, who reported the use of water as solvent for cyclocondensations of iminium salts (Larsen and Grieco, 1985). Known as being a very energy demanding reaction, the retro Diels-Alder process is usually not considered as a competitive pathway in most Diels-Alder... 

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