Diels-Alder cycloadducts

Less reactive dienes such as cyclohexadiene can be employed efficiently, giving the adduct in 90% yield in 93% ee. Acyclic dienes such as piperylene, 2,4-hexadiene, and 1-phenylbutadiene also react with the acryloyloxazolidinone derivative to afford Diels-Alder cycloadducts in high optical yields (Scheme 1.38, Table 1.17). 

The endo exo selectivity for the Lewis acid-catalyzed carbo-Diels-Alder reaction of butadiene and acrolein deserves a special attention. The relative stability of endo over exo in the transition state accounts for the selectivity in the Diels-Alder cycloadduct. The Lewis acid induces a strong polarization of the dienophile FMOs and change their energies (see Fig. 8.2) giving rise to better interactions with the diene, and for this reason, the role of the possible secondary-orbital interaction must be considered. Another possibility is the [4 + 3] interaction suggested by Singleton... 

Careful chromatographic and detailed HNMR spectroscopic analysis of the products from the thermolyses of ethyl azidoformate in o-, m- and p-xylene revealed in all cases a mixture of 1 //-azepines.80 In o-xylene, only two of the four possible isomers were separated and characterized, namely, ethyl 4,5-dimethy 1-1 //-azepine-1 -carboxylate (9 %) and ethyl 3,4-dimethyl-l H-azepine-1-carboxylate (7 %). w-Xylene yielded a 2 3 mixture of ethyl 3,5-dimethyl-l//-azepine-1-carboxylate and ethyl 2,4-dimethyl-l//-azepine-l-carboxylate. The 2,4-dimethyl isomer (20 %) can be isolated from the mixture by removal of the 3,5-dimethyl isomer as its Diels-Alder cycloadduct with ethenetetracarbonitrile. p-Xylene gave a mixture of the two possible isomeric azepines which were partially separated by column chromatography. A pure sample of ethyl 2,5-dimethyl-1//-azepine-1-carboxylate (26%) was obtained from the mixture by selective decomposition of the 3,6-dimethyl isomer with refluxing alcoholic potassium hydroxide. 

Oxidation of the 2//-4a,7-dihydro derivative 15, the inverse electron-demand [4+2] Diels-Alder cycloadduct of ethyl 1 /7-azepine-l -carboxylate and dimethyl l,2,4,5-tetrazine-3,6-dicar-boxylate, with tetrachloro-l,4-bcnzoquinone furnishes the pyridazino[4.5-r/]azepine 16.112... 

In contrast LP-DE gives disappointing results for intramolecular imino Diels-Alder reactions, even in the presence of CSA. This is due to the fact that weak acids become strong acids in highly polar media such as 5.0m LP-DE and the protonation of diene, with concomitant diene isomerization, competes with cycloaddition [42]. This observation was supported by using trifluoroacetic acid (TEA). The imine 33 (Scheme 6.21) in LP-DE at room temperature in the presence of TEA gave a 1 1 mixture of cycloadduct 34 and the isomerized diene 35 within the unreacted imine 33. No Diels-Alder cycloadduct 36 was detected. 

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. ... 

Based on the high dienophilicity of acyclic vinyl sulfones one should expect thiete dioxides to exhibit similar properties. Indeed, several Diels-Alder (2 + 4) cycloadditions with thiete dioxide as dienophile are known. For example, 1,3-butadiene and 1,3-diphenylisobenzofuran react with 3-chloro- or 3-bromo-thiete dioxides to afford the corresponding 1 1 Diels-Alder cycloadducts (equation 105). 

PM3 semi-empirical calculations on 67 supported the experimentally observed formation of the [2+2] cycloaddition product rather than a [4+2] Diels-Alder cycloadduct. The calculations indicate that the oxaphosphete ring is... 

To demonstrate the effectiveness of this scavenger, it was successfully applied in the synthesis of eight different flavonoid Diels-Alder cycloadducts (Scheme 7.130b). The two-step microwave-mediated procedure furnished the desired compounds in high yields and excellent purities. 

Surprisingly, the aromatic product is not obtained in the reaction with fumaroni-trile (47) - the Diels-Alder cycloadduct is the only product. The activation barriers calculated for this aromatization were the highest reported in this work [52],... 

Cycloadditions selectively afford the adducts on the 6,6-ring junctions [65], and the products occasionally undergo a facile retro-Diels-Alder reaction as a consequence of the low thermodynamic stability of the adduct. Very stable Diels-Alder cycloadducts have, however, been prepared by use of different substituted o-quinodimethanes, probably because of stabilization by aromatization of the resulting adducts [66],... 

The interplay of crystal packing, migrational aptitudes, and solid-state reactivity maybe demonstrated with the reactivities of the Diels-Alder cycloadducts of maleic anhydride and cyclopentadiene (1 and 2) or cyclohexadiene (3). 

Scheme 3 Synthesis of Diels-Alder cycloadducts using an ionic liquid as homogeneous support...

This French group (145) has also been able to divert the usual Diels-Alder cycloaddition pathway of Reissert salts with oleftnic esters to a 1,3-dipolar cycloaddition pathway by the addition of triethylamine. In addition, mtinchnone imine 243 can be trapped with dipolarophiles to furnish 244 (146). No Diels-Alder cycloadducts derived from the oxazolium salt were detected. In contrast, fumarate... 

The use of 4-heteroarylmethylene- and 4-aryhnethylene-5(47/)-oxazolones as dienophiles in the Diels-Alder reaction has been recently reviewed. More recently the reactivity of the exocyclic double bond of 4-(alkoxymethylene)-5(4//)-oxazolones with several dienes has been assessed. Reaction of 4-(methoxymethyl-ene)-2-phenyl-5(477)-oxazolone and 1,3-butadiene requires the presence of Et2AlCl as a catalyst and even then the Diels-Alder cycloadduct is obtained in low yield. 

Desimoni and co-workers were able to produce either enantiomer (2R or 25) of the Diels-Alder cycloadduct using the same isomer of phe-box ligand ent-6 under different reaction conditions (Fig. 9.25, Table 9.11)." " They found that when using magnesium(II) perchlorate as the metal source, the reaction produced cycloadduct in >98% yield with an endo/exo ratio of 93 7 and an endo ee of 70% for the (25) isomer. In contrast, when magnesium(II) perchlorate was used in the presence of 2 equiv of water, the reaction afforded the cycloadduct again in >98% yield with an endo/exo ratio of 93 7, but in this instance, the endo ee was 65% for the (2R) isomer. This selectivity difference was explained by a change in... 

Using a diene, the reaction can proceed through the ene pathway as above, or through the hetero-Diels-Alder pathway. For example, the condensation of 2,3-dimethyl-1,3-butadiene 103 with glyoxylate esters 99, 104, and 105 can proceed to form either a hetero Diels-Alder cycloadduct 106 or an ene product 107 (Fig. 9.35). 

It has been shown that complete selectivity for the hetero-Diels-Alder cycloadduct 109 (100% endo, 60% ee) can be achieved in the hetero-Diels-Alder reaction of 1,3-cyclohexadiene 108 and ethyl glyoxylate 99 using ent-6 and copper(II) triflate derived catalyst complex. Another interesting reaction introduced by Jprgensen and co-workers was the reaction between 1,3-cyclohexadiene 108 and diethyl ketomalonate 110 to form cycloadduct 111 in 76% yield with an ee of 84% (Fig. 9.35b, p. 558). ... 

Treatment of 4,5-bis(bromomethyl)-3-phenylisoxazole (375) with sodium iodide and subsequently with azodicarboxylate gave Diels-Alder cycloadduct (377) (91TL4603). Intermediate 1,2-quinodime-thyde (376) may participate in the reaction as an active 1,3-diene. 

The Diels-Alder cycloadduct of furan and maleic anhydride has played a key role in a new synthesis of butenolides (79S607). Treatment of the cycloadduct (24) with methanol affords a half acid ester which is reacted in turn with an excess of a Grignard reagent to produce the lactone (25) on acidic work-up. On heating this lactone at 150-180 °C, thermal fragmentation takes place to yield the 4,4-dialkylbutenolide (26) in high overall yield (Scheme 5). 

Density functional theory computational studies have been used to determine die importance of secondary orbital interactions for the stability of transition-state structures for die 4 + 2-cycloaddition of furan with cyclopropene.175 Kinetic studies of die 2 + 4-cycloaddition of 2-cyclopropylidene acetates with furan and dimethylful-vene suggest a mechanism involving diradicals or zwitterions as intermediates.176 Cyclopropene, produced by die reaction of allyl chloride with sodium bis(bimediyl-silyl)amide, reacts with 1,3-diphenylisobenzofuran to produce both endo- and exo-Diels-Alder cycloadducts isolated for the first tune.177... 

Furthermore, they have reported the preparation of aza-Diels-Alder cycloadducts (I and II, Fig. 14) arising from a useful dual Diels-Alder behavior. Imines derived from 4-oxoazetidine-2-carbaldehydes have been found to behave as aza-dienophiles with the Danishefsky s reagent, and as azadiene with alkenes [275]. 

The versatility and selectivity of the Lawesson reagent is also evidenced in the synthesis of the highly complex alkaloid 19-hydroxytubotaiwine287, in which a ketolactam is transformed into a thionethiolactam (equation 41). Also, Diels-Alder cycloadducts can be thionated with 52 and, upon thermolysis at high temperatures (FVT), afford the corresponding thioketenes which are trapped in situ2m (equation 42). 

In situ combination of Lawesson reagent and anthracene allows reactive thioaldehy-des to be formed and subsequently trapped as Diels-Alder cycloadducts, as illustrated in the case of pentafluorothiobenzaldehyde289 (equation 43), which is very reactive and polymerizes rapidly. 

The reaction of the highly stable l-substituted-3-(2-nitrovinyl) indoles with DMAD affords aromatic carbazoles by elimination of nitrous acid from the primary Diels-Alder cycloadduct (93JHC183). 

Dimethyl acetylenedicarboxylate reacted slowly with 3-vinylthiophene 78 to give a mixture of two major products, 79 and 80. A small amount of a mixture, which could be the Z and E ethenedioates 81, was formed by ene addition to the initial Diels-Alder cycloadduct (87T269). 

Vinylbenzothiophenes also react with acetylenic compounds as diene systems in reactions reported in the literature. One example is the reaction of 2-vinylbenzo[6]thiophene with DMAD and with dibenzoylacetylene, affording the corresponding Diels-Alder cycloadducts [89IJC(B)724]. 

The vinyl function can be incorporated into a carbocyclic ring. In this context the reactivity of the readily available 3-(l-cyclohexenyl)indole 46 toward different dienophiles was studied (91LA357). In some cases (DMAD, NPMI) the Diels-Alder cycloadducts were obtained (Sections II,A,4 and II,C,4) however, reaction with DEAZD and PTAD afforded the ene adducts 254 and 255. 

As l,2,4-triazole-3,5-dione (PTAD) is a stronger dienophile than acetylenic esters, more facile formation of the Diels-Alder cycloadducts was expected. But because it cannot behave as a diene in a reaction with alkynes such as diethyl azodicarboxylate, the formation of dihydrooxadia-zines is excluded. In spite of these characteristics, no Diels-Alder adducts were obtained in the reaction of l-phenyl-4-vinylpyrazole with PTAD in acetone at -80°C and 2,2-dimethyl-4(l-phenylpyrazol-4-yl)-8-phenyl-l,6,8-triaza-3-oxabicyclo[4.3.0]nona-7,9-dione 277 was obtained as a major product. The isolation of the tetrahydrooxadiazine 277 indicates that the 1,4-dipole 278 was formed and trapped with acetone. 

In contrast with the reactivity of 4-vinylpyrazoles with PTAD which involve just the oleiinic double bond, l-phenyl-5-vinylpyrazole reacted with PTAD as a diene, affording the Diels-Alder cycloadduct 281 [90JCS(P1)2749]. 

A new and readily available catalytic system has been developed to open the cyclopropane ring in 4 + 2-1- 2-homo-Diels-Alder cycloadducts formed by reaction of norbornadienes and buta-1,3-diene.47 The cobalt-mediated homo-Diels-Alder reaction followed by this PtCB-promolcd isomerization is a key step in the efficient route to bicyclo[5.3.0]decanes. 

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