Diels-Alder reactions elimination sequence

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. 

The presence of the catalyst can also favor multiple Diels-Alder reactions of cycloalkenones. Two typical examples are reported in Schemes 3.6 and 3.7. When (E)-l-methoxy-1,3-butadiene (14) interacted with 2-cyclohexenone in the presence of Yb(fod)3 catalyst, a multiple Diels-Alder reaction occurred [21] and afforded a 1 1.5 mixture of the two tricyclic ketones 15 and 16 (Scheme 3.6). The sequence of events leading to the products includes the elimination of methanol from the primary cycloadduct to afford a bicyclic dienone that underwent a second cycloaddition. Similarly, 4-acetoxy-2-cyclopenten-l-one (17) (Scheme 3.7) has been shown to behave as a conjunctive reagent for a one-pot multiple Diels-Alder reaction with a variety of dienes under AICI3 catalysis, providing a mild and convenient methodology to synthesize hydrofluorenones [22]. The role of the Lewis acid is crucial to facilitate the elimination of acetic acid from the cycloadducts. The results of the reaction of 17 with diene... 

What is described as a domino Knoevenagel-hetero-Diels-Alder reaction , involving the reaction of the glucose-derived aldehyde 93 with a 1,3-dicarbonyl compound in presence of either proline or ethylenediammonium acetate, leads to the doubly annulated 5 6 6-fused compound 94 (Scheme 30) <2004S1150>. If the dicarbonyl compound is Meldmm s acid, however, the sequence is completed by spontaneous elimination of acetone and carbon dioxide from the Diels-Alder adduct, to give compound 95 <2005ASC1353>. 

In a rather elegant approach towards colombiasin A (36) Flynn et al. [47] would access the tetracyclic carbon skeleton through an enantioselective intermolecular Diels-Alder sulfoxide elimination-intramolecular Diels-Alder (DA-E-IMDA) sequence between double-diene 166 and quinone 167 (Scheme 26). A key element of the proposed approach would be the chiral sulfoxy group in 167 which controls both the regio and facial selectivity of the intermolecular Diels-Alder reaction and eliminates generation of the dienophile for the IMDA reaction. 

In addition to the reaction of vinylcarbene complexes with alkynes, further synthetic procedures have been developed in which Fischer-type carbene complexes are used for the preparation of benzenes. Most of these transformations are likely to be mechanistically related to the Dbtz benzannulation reaction, and can be rationalized as sequences of alkyne-insertions, CO-insertions, and electrocycli-zations. A selection of examples is given in Table 2.18. Entry 4 in Table 2.18 is an example of the Diels-Alder reaction (with inverse electron demand) of an enamine with a pyran-2-ylidene complex (see also Section 2.2.7 and Figure 2.36). In this example the adduct initially formed eliminates both chromium hexacarbonyl ([4 -I- 2] cycloreversion) and pyrrolidine to yield a substituted benzene. 

Few examples of the preparation of six-membered heteroaromatic compounds using Fischer-type carbene complexes have been reported [224,251,381]. One intriguing pyridine synthesis, reported by de Meijere, is sketched in Figure 2.35. In this sequence a (2-aminovinyl)carbene complex first rearranges to yield a complexed 1 -azadiene, which undergoes intermolecular Diels-Alder reaction with phenylacetylene. Elimination of ethanol from the initially formed adduct leads to the final pyridine. 

A further useful reaction sequence, reported by Aumann [219], is based on the Diels-Alder reaction of 2-pyranylidene complexes with enamines (Figure 2.36). Retro-Diels-AIder reaction of the initially formed 3-oxabicycIo[2.2.2]octan-2-ylidene complex leads to elimination of metal hexacarbonyl and formation of a substituted cyclohexadiene. Although this sequence can also be performed with the corresponding carbonyl compounds (2//-2-pyranones), these normally... 

At higher temperatures retro-Diels-Alder reaction may also occur in the opposite sense to addition, as in the reaction of methyl pyrrole-1-carhoxylate with dimethyl acetylenedicarboxylate at 200°, which affords acetylene and the pyrrole triester (56). The decomposition of the suspected intermediate Diels-Alder adduct (11) at 170° has been separately established. Compounds 19 and 20 are intermediates in similar addition-elimination reactions leading to pyrrole-l,3,4-triesters, in which removal of acetylene from the system makes the reaction sequence effectively irreversible. 

Danishefsky dienes [98] cycloadd to Cjq in refluxing toluene or benzene [5, 38, 99-101]. The diene 103 adds in 60% yield to Cjq to give the desilylated ketone 104 [5,101]. Acid-catalyzed methanol elimination then furnishes the enone 105 in 82% yield (Scheme 4.17). As already described, this enone can be reduced by DIBAL-H to the corresponding alcohol for further functionalization. The same a,(3-un-saturated alcohol can also be obtained in better yield by Diels-Alder reaction of Cg0 with butadiene, followed by oxidation with singlet oxygen to the allylic hydroperoxide and PPhj reduction to the desired alcohol [101]. This sequence yields the allylic alcohol in 53%, starting from Cjq without the need of isolating intermediates. 

Steroidal, alicyclic or aromatic annulated pyridines were prepared via a microwave-assisted, base-catalyzed Henry reaction of /1-formyl enamides and nitromethane on an alumina support [97]. Highly substituted tri- and tetrasubstituted pyridines were synthesized in a Bohlmann-Rahtz reaction from ethyl /3-amino crotonate and various alkynones. The reaction involved a Michael addition-cyclodehydration sequence and was effected in a single synthetic step under microwave heating conditions [98]. An alternative approach towards polysubstituted pyridines was based on a reaction sequence involving an inverse electron-demand Diels-Alder reaction between various enamines 45 and 1,2,4-triazines 44 (Sect. 3.6), followed by loss of nitrogen and subsequent elimination-aromatization. Enamines 45 were formed in situ from various ketones and piperidine under one-pot microwave dielectric heating conditions [99]. Furthermore, a remarkable acceleration of the reaction speed (from hours and days to minutes) was observed in a microwave-assisted cycloaddition. Unsymmetrically substituted enamines 45 afforded mixtures of regioisomers (Scheme 35). 

Anodic dehydrogenations, e.g., oxidations of alcohols to ketones, have been treated in Sect. 8.1 and formation of olefins by anodic elimination of C02 and H+ from carboxylic acids was covered in Sect. 9.1. Therefore this section is only concerned with anodic bisdecarboxylations of v/odicarboxylic acids to olefins. This method gives usually good results when its chemical equivalent, the lead tetraacetate decarboxylation, fails. Combination of bisdecarboxylation with the Diels-Alder reaction or [2.2] -photosensitized cycloadditions provides useful synthetic sequences, since in this way the equivalent of acetylene can be introduced in cycloadditions. 

A convenient method for the synthesis of annulated 2-alkylthio-5-aminofurans has been described by Padwa et al. The reaction sequence involves the formation of a thionium group from readily available dithioacetals upon treatment with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF). The thionium ion undergoes cyclization with the 7-carbonyl group followed by an elimination step to yield the 2,3,5-trisubstituted furans in good to excellent yields (Equation 29) <2002JOC1595>. The alkylthioaminofuran reaction products can be utilized to constmct polyclic frameworks of natural products in a subsequent Diels-Alder reaction. 

Cycloaddition reaction of triethyl 1,3-5-triazinetricarboxylate (585) with 1,1-diamino-ethene, which is generated in situ from acetamidine hydrochloride, provides an adduct (586) which subsequently eliminates ammonia (587) and undergoes a retro Diels-Alder reaction with loss of ethyl cyanoformate, thereby forming the pyrimidine (588). The reaction sequence is highly dependent... 

Deoxyloganin (24) has previously been synthesized by Tietze and coworkers, utilizing an intramolecular hetero-Diels-Alder reaction to construct the iridoid core (Scheme 10). The synthesis commenced with conversion of (5)-citronellal (47) to enol ether 48 in seven steps. Knoevenagel condensation of the aldehyde with Meldrum s acid, followed by in situ intramolecular hetero-Diels-Alder reaction afforded pyran 49, with all the carbons required for the natural product core installed. Conversion of 49a, via methanolysis and a reduction/elimination sequence, to lactol acetate 50, was achieved in four steps. Finally, glycosylation and deprotection provided the natural product in a total of 14 steps. 

Another potentially powerfnl sequence arises by combining one or two intramolecular Heck-type couplings with an intra- or intermolecular Diels-Alder addition (for early examples of inter-intermolecular one-pot domino Heck-Diels-Alder reactions see Refs. [49] and [50]). An all-intramolecular version of such a sequence has been shown to proceed reasonably smoothly for terminally alkoxycarbonyl-substituted 2-bromotrideca-l,ll-dien-6-ynes under palladium catalysis at 130 °C. At 80 °C, the sequential reaction stops after the two consecutive Heck-type cyclizations and subsequent /3-hydride elimination to give a 1,3,6-triene apparently only the ( )-isomer undergoes the intramolecular Diels-Alder reaction, as the (Z)-l,3,6-triene is observed accompanying the tetracyclic system obtained at 130 °C (Scheme 36). 

A domino sequence comprising a cycloaddition and subsequent cycloreversion step can often find a more general application in organic synthesis, especially in the formation of aromatic compounds such as furans or pyrroles. Oxazole moieties as electron-deficient dienes often serve as the crucial reactive centers which cycloadd to a triple bond and eliminate a nitrile upon cycloreversion. If the first step is intramolecular, the impelling enthalpy preserved in the stability of the formed CN function is additionally accompanied by a positive entropy when the nitrile, sometimes volatile, leaves the substrate. In an older example from 1984 [10], Jacobi and coworkers devised a scheme for the preparation of a highly substituted furan on their synthetic way to paniculide A. An intramolecular Diels-Alder reaction was followed by the critical extrusion of volatile acetonitrile, furnishing the bicycle 8 in 94% yield (Scheme 6.2). 

The domino reaction started with an intramolecular hetero-Diels-Alder reaction of 215 to give 218, which was followed by elimination of molecular nitrogen to form the 1,3-dipole 219. The final step in the sequence was an intramolecular [3 + 2]-cycloaddition to provide rac-216 in 71% yield as a single diastereomer. Compound... 

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