Diels-Alder reactions, with ether

Intermolecular [4C+2S] cycloaddition reactions where the diene moiety is contained in the carbene complex are less frequent than the [4S+2C] cycloadditions summarised in the previous section. However, 2-butadienylcarbene complexes, generated by a [2+2]/cyclobutene ring opening sequence, undergo Diels-Alder reactions with typical dienophiles [34,35] (Scheme 59). Also, Wulff et al. have described the application of pyranylidene complexes, obtained by a [3+3] cycloaddition reaction (see Sect. 2.8.1), in the inverse-electron-demand Diels-Alder reaction with enol ethers and enamines [87a]. Later, this strategy was applied to the synthesis of steroid-like ring skeletons [87b] (Scheme 59). 

Azadienes undergo Diels-Alder reactions to form pyridine, dihydro- and tetrahydropyridine derivatives. N-Vinyl lactim ethers undergo Diels-Alder reactions with a limited set of dienophiles. " Thioketones react with dienes to give Diels-Alder cycloadducts. The carbonyl group of lactams have also been shown to be a dienophile. Certain heterocyclic aromatic rings (among them furans) can also behave as dienes in the Diels-Alder reaction. Some hetero dienes that give the reaction are -C=C-C=0, 0=C-C=0, and N=C-C=N. ... 

In 1996, the first successful combination of an enzymatic with a nonenzymatic transformation within a domino process was reported by Waldmann and coworkers [6]. These authors described a reaction in which functionalized bicy-clo[2.2.2]octenediones were produced by a tyrosinase (from Agaricus bisporus) -catalyzed oxidation of para-substituted phenols, followed by a Diels-Alder reaction with an alkene or enol ether as dienophile. Hence, treatment of phenols such as 8-1 and an electron-rich alkene 8-4 in chloroform with tyrosinase in the presence of oxygen led to the bicyclic cycloadducts 8-5 and 8-6 in moderate to good yield (Scheme 8.1). It can be assumed that, in the first step, the phenol 8-1 is hydroxylated by tyrosinase, generating the catechol intermediate 8-2, which is then again oxidized enzy-... 

Today, multi-parallel synthesis lies at the forefront of organic and medicinal chemistry, and plays a major role in lead discovery and lead optimization programs in the pharmaceutical industry. The first solid-phase domino reactions were developed by Tietze and coworkers [6] using a domino Knoevenagel/hetero-Diels-Alder and a domino Knoevenagel/ene protocol. Reaction of solid-phase bound 1,3-dicarbonyl compounds such as 10-22 with aldehydes and enol ethers in the presence of piperidinium acetate led to the 1-oxa-1,3-butadiene 10-23, which underwent an intermolecular hetero-Diels-Alder reaction with the enol ethers to give the resin-bound products 10-24. Solvolysis with NaOMe afforded the desired dihydro-pyranes, 10-25 with over 90 % purity. Ene reactions have also been performed in a similar manner [7]. 

The preparation of resin-bound nitroalkenes via a microwave-assisted Knoevenagel reaction of resin-bound nitroacetic acid with aryl and alkyl substituted aldehydes is reported. The potential of these resin-bound nitroalkenes for application in combinatorial chemistry is demonstrated by a Diels-Alder reaction with 2,3-dimethylbutadiene (Scheme 8.9). It is also used for one-pot three-component tandem [4+2]/[3+2] reactions with ethyl vinyl ether and styrene 46... 

Lewis acid catalysis enormously enriches the scope of Diels-Alder reactions, but it is limited to reagents containing Lewis basic sites, i.e. functional groups with lone pairs such as carbonyl, amino, ether or nitro close to the reaction centre. As we have seen in the discussion about the FMO aspects of Lewis acids, the major reason for catalysis is the reduction of the HOMO-LUMO gap. In case of Diels-Alder reactions with normal electron demand, it follows that the coordination of the Lewis acid lowers the LUMO energy of the dienophile. Such interactions are only possible if there is a spatial proximity or an electronic conjugation between the coordinated Lewis basic site and the reaction centre. Fortunately, in nearly every Diels-Alder reaction one of the reagents, mostly the dienophile, meets this requirement. 

A similar enantiomer-selective activation has been observed for aldol " and hetero-Diels-Alder reactions.Asymmetric activation of (R)-9 by (/f)-BINOL is also effective in giving higher enantioselectivity (97% ee) than those by the parent (R)-9 (91% ee) in the aldol reaction of silyl enol ethers (Scheme 8.12a). Asymmetric activation of R)-9 by (/f)-BINOL is the key to provide higher enantioselectivity (84% ee) than those obtained by (R)-9 (5% ee) in the hetero-Diels-Alder reaction with Danishefsky s diene (Scheme 8.12b). Activation with (/ )-6-Br-BINOL gives lower yield (25%) and enantioselectivity (43% ee) than the one using (/f)-BINOL (50%, 84% ee). One can see that not only steric but also electronic factors are important in a chiral activator. 

Aiming at the pyranose form of sugars, normal type hetero-Diels-Alder reactions were extensively used for the synthesis of functionally substituted dihydropyran and tetrahydropyran systems (5-10) (see routes A - D in the general Scheme 1) which are also important targets in the "Chiron approach" to natural product syntheses (2.) Hetero-Diels-Alder reactions with inverse electron demand such as a, p-unsaturated carbonyl compounds (l-oxa-1,3-dienes) as heterodienes and enol ethers as hetero-dienophiles, are an attractive route for the synthesis of 3,4-dihydro-2H-pyrans (11). 

The synthesis of a range of benzoxazines (35) from 34 using AgBp4 in anhydrous ether has been described . Thermolysis of these in a melt resulted in a retro-Diels-Alder reaction with loss of formaldehyde giving the azaxylylenes (36), which undergo spontaneous electrocyclization to give the 2-aIkyl-41/-3,1-benzoxazines (37) in excellent yields (Scheme 5). 

The reactivity of the produced complexes was also examined [30a,b]. Since the benzopyranylidene complex 106 has an electron-deficient diene moiety due to the strong electron-withdrawing nature of W(CO)5 group, 106 is expected to undergo inverse electron-demand Diels-Alder reaction with electron-rich alkenes. In fact, naphthalenes 116 variously substituted at the 1-, 2-, and 3-positions were prepared by the reaction of benzopyranylidene complexes 106 and typical electron-rich alkenes such as vinyl ethers, ketene acetals, and enamines through the Diels-Alder adducts 115, which simultaneously eliminated W(CO)6 and an alcohol or an amine at rt (Scheme 5.35). 

The benzoxazoles 59 and 60 can act as azadienes in Diels-Alder reactions with nucleophilic alkenes such as vinyl ethers <98JCS(P1)3389>. ... 

Pyrrolo[2,3- ]pyridinones, 59, undergo an inverse electron demand Diels-Alder reaction with ethyl vinyl ether to generate 6-aza-5-carboline products in excellent yields but low stereoselectivity (Equation 4) <1997S73>. 

Httero-Diels-Alder reactionAcrolein undergoes a Diels-Alder reaction with furanoid and pyranoid exocyclic vinyl ethers at 25 (4 6 days). The spirokelal (2) obtained can be oxidized in CHiOH by w-chloroperbenzoic acid to the ring... 

Diels-Alder reactions with p-quinones (6. 65 66). The orientation of Diels-Alder reactions of 6-meihoxy-l-vinyl-3,4-dihydronaphthalene (1) with p-quinones is subject to reversal by addition of BF, etherate (1.3 equivalent). Thus the thermal reaction with 2,6-dimethyl-/>-bcnzoquinone (2) results in exclusive formation of 3, whereas the catalyzed reaction leads predominately to the isomer 4. The adduct 3 is stable to base, but the syn, m-isomer 4 on treatment with NaX O, is converted to the more stable anti, frau.s-isomer 5. 

Hetero-Diels-Alder reaction with inverted electron demand between a, 3-unsatu-rated carbonyl compounds (1-oxa-l,3-butadienes 11 Scheme 6) and enol ethers provides an access to 6-alkoxy-3,4-dihydro-2/f-pyrans 12 [31,32]. These heterocycles are also useful... 

Iodobenzyl propargyl ether 57 cyclizes with 7t-allylpalladium (Scheme 18) to form after trapping by a secondary amine tetrahydro-2-benzoxepines 58 in 70% yield. The piperidino derivative 58 (R2 = (CH2)5) undergoes Diels-Alder reaction with 4-phenyl-l,2,4-triazole-3,5-dione as dienophile to give a spiro derivative 59 in 44% yield <1996TL6565>. 

Diels-Alder reaction with cyclopentadienes. An improved synthesis of a key intermediate (6) to gibberellic acid (7) begins with the cycloaddition of 1 to a 2 1 mixture of 2- and l-(2-bromoallyl)cyclopentadiene (2) to give the adduct 3 in which the acetyl group has the enr/o-orientation. The silyl enol ether of 3 when heated undergoes a Cope rearrangement to give a eis-hydrindene (4), which was converted... 

This three-component reaction as the key step of this synthesis is called a domino-Knoevenagel-hetero-Diels-Alder reaction. Domino reactions are defined as processes of two or more bond forming reactions in which a subsequent transformation takes place by virtue of the functionalities introduced in a former transformation.2,16 The tetrahydrocarbolinaldehyde 11 first reacts in a Knoevenagel type condensation with Meldrum s acid 14 and ethyleneammonium diacetate 41 as the catalyst to oxabutadiene 44 which then undergoes a Diels-Alder reaction with enol ether 13. 

A DFT study of the polar Diels-Alder reaction of 4-aza-6-nitrobenzofuroxan with cyclopentadiene found only one highly asynchronous transition state structure associated with the formation of the 4 + 2-adduct.178 4-Nitrobenzodifuroxan has been shown to be a highly reactive nitroalkene in Diels-Alder reactions with common dienes (cyclopentadiene) to produce stable NED adducts and with ethyl vinyl ether to produce IED adducts.179 Unlike a-acylfuran, 2-nitrofurans have been shown to be active dienophiles in thermal NED Diels-Alder reactions with a variety of buta-1,3-dienes, including Danishefsky s diene.180... 

The reactivity of 47/-benzopyran-4-ones in Diels-Alder reactions is well documented <1987T3075>, and recently high asymmetric induction has been achieved in the reaction of 3-alkoxycarbonyl-substituted chromones with chiral auxiliaries and Danishefsky s diene <1991JOC2058>. It should be noted that 3-formylchromones can react as heterodienes in the stereoselective inverse electron Diels-Alder reaction with enol ethers <1994T11755> to provide a route to pyrano[4,3-A][l]benzopyrans a heterocyclic nucleus which occurs naturally in the fungal metabolite fulvic acid <1984CC1565>. The thermal Diels-Alder reaction of 477-pyran-4-one 405 in the presence of an excess of Danishefsky s diene 404 provided cycloadduct 406 (Equation 32) <1996H(43)745>. 

Oxidation of the o/T/zo-substituted acetanilides 324 with DMP leads to the isolable o-iminobenzoquinones 325 (Scheme 94) (02JA2221). The imino-quinones undergo inverse electron demand Diels-Alder reactions with the vinyl ether and vinyl sulfide shown in Scheme 94, thus providing access to the benzoxazine derivatives 326 and 327. 

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