Ethyl Diels-Alder with

In the case of 1,3-diphenylisoindole (29), Diels-Alder addition with maleic anhydride is readily reversible, and the position of equilibrium is found to be markedly dependent on the solvent. In ether, for example, the expected adduet (117) is formed in 72% yield, whereas in aeetonitrile solution the adduet is almost completely dissociated to its components. Similarly, the addition product (118) of maleic anhydride and l,3-diphenyl-2-methjdi.soindole is found to be completely dissociated on warming in methanol. The Diels-Alder products (119 and 120) formed by the addition of dimethyl acetylene-dicarboxylate and benzyne respectively to 1,3-diphcnylisoindole, show no tendency to revert to starting materials. An attempt to extrude carbethoxynitrene by thermal and photochemical methods from (121), prepared from the adduct (120) by treatment with butyl-lithium followed by ethyl chloroform ate, was unsuccessful. 

A great number of N-substituted 4-hydroxy-3-nitro-l,8-naphthyridin-2 (IH)-ones are obtained by reaction of N-substituted azaisatoic anhydrides with ethyl nitroacetate carbanion (Section II,A,4,a). A very specific method, more recently developed, is that of the inverse Diels-Alder method, involving the reactions of enamines with 5-nitropyrimidine (Section II,A,4,b). 

The Diels-Alder reactions of the methyl or ethyl ester of benzenesulfonylindole-2-acrylic acid with several l-alkoxycarbonyl-l,2-dihydropyridines are reported and only a single stereoisomer was obtained, as in the case of l-methoxy(ethoxy)-carbonyl-1,2-dihydropyridines. However, when the Diels-Alder reaction of 17 was carried out with 8g[R = (CHsjsC], a mixture of two stereoisomers 18gand25were obtained in a 1 1 ratio (65% total yield). The bulky rerr-butyl group creates sufficient steric interference with the indole ring to cause the loss of stereochemistry ... 

Functionalized nitroalkenes are important chenophiles in the Diels-Alder ri example, fE -methyl fi-nitroactylate is an impottant reagent in organic synthesis The nitre group can be readily eliminated the Diels-Alder reaction of fi-nitroactylate is equivalent to that of ethyl propiolate with an inverse regiochemistry fEq. 8.4. ... 

Reaction of isoprene (2-methyl-l,3-butadiene) with ethyl propenoate gives a mixture of two Diels-Alder adducts. Show the structure of each, and explain whv a mixture is formed. 

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. 

The inverse electron-demand Diels-Alder cycloaddition of ethyl l//-azepine-l-carboxylate (1) with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylatc (36) yields the C4 —C5 adduct 37.266... 

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... 

Ethyl H-, 2-diazepine-l-carboxylate functions as a 2 -component in the Diels-Alder reaction with tetrachloro-l,2-benzoquinone to give a mixture of the regioisomers 20 and 21.100... 

Diels-Alder cycloaddition of 3,4-bis(trifluoromethyl)furan with ethyl propynoate involved addition of two a,/3-unsaturated esters followed by acid-catalyzed ring opening, rearrangement, and elimination of ethanol to give a 6,7-bis(trifluoromethyl)isocoumarin-3-carboxylate [92JFC(56)359]. 

The synthesis of chaparrinone and other quassinoids (naturally occurring substances with antileukemic activity) is another striking example [16a-c]. The key step of synthesis was the Diels-Alder reaction between the a,/l-unsaturated ketoaldehyde 1 (Scheme 6.1) with ethyl 4-methyl-3,5-hexadienoate 2 (R = Et). In benzene, the exo adduct is prevalent but it does not have the desired stereochemistry at C-14. In water, the reaction rate nearly doubles and both the reaction yield and the endo adduct increase considerably. By using the diene acid 2 (R = H) the reaction in water is 10 times faster than in organic solvent and the diastereoselectivity and the yield are satisfactory. The best result was obtained with diene sodium carboxylate 2 (R = Na) when the reaction is conducted 2m in diene the reaction is complete in 5h and the endo adduct is 75% of the diaster-eoisomeric reaction mixture. 

Earle and coworkers [54] have performed Diels-Alder reactions in neutral ionic liquids. The results of reactions of cyclopentadiene with dimethyl maleate, ethyl acrylate and acrylonitrile are reported in Table 6.10. The cycloadditions proceeded at room temperature in all of the ionic liquids tested, except [BMIMJPF4, and gave almost quantitative yields after 18-24h. The endo/exo selectivity depends on dienophile. No enantioselectivity was observed in the [BMIM] lactate reaction. 

The results of Diels-Alder reactions of cyclopentadiene with diethyl fumarate, diethyl maleate and ethyl acrylate carried out in SC-H2O are reported in Scheme 6.32 [79]. The cycloaddition of diethyl fumarate occurred with low yield. 

The Diels Alder reactions of maleic anhydride with 1,3-cyclohexadiene, as well the parallel reaction network in which maleic anhydride competes to react simultaneously with isoprene and 1,3-cyclohexadiene [84], were also investigated in subcritical propane under the above reaction conditions (80 °C and 90-152 bar). The reaction selectivities of the parallel Diels-Alder reaction network diverged from those of the independent reactions as the reaction pressure decreased. In contrast, the same selectivities were obtained in both parallel and independent reactions carried out in conventional solvents (hexane, ethyl acetate, chloroform) [84]. 

Chemoselective alkenylation in the C-3 position of N-substituted 3,5-dichloropyrazin-2(lH)-ones has been described by Van der Eycken et al. [27]. When a mixture of N-substituted 3,5-dichloropyrazin-2(lH)-one, ethyl acrylate, and NEts in DME, using Pd(OAc)2/DTPB [2-(di-f-butylphosphanyl)bi-phenyl] as a precatalyst, was irradiated for 15 min at 150 °C, the desired /1-fimctionabzed ethyl acrylates could be obtained in moderate yields (Scheme 81). When styrene was used as an alkene, a mixture of E and Z products was isolated. The type of catalyst used proved to be important to avoid competitive Diels-Alder reaction of ethyl acrylate with the hetero-diene system of 3,5-dichloro-l-benzylpyrazin-2(lH)-one. 

An interesting parallel was found while the microwave-enhanced Heck reaction was explored on the C-3 position of the pyrazinone system [29]. The additional problem here was caused by the capability of the alkene to undergo Diels-Alder reaction with the 2-azadiene system of the pyrazinone. An interesting competition between the Heck reaction and the Diels-Alder reaction has been noticed, while the outcome solely depended on the substrates and the catalyst system. Microwave irradiation of a mixture of pyrazinone (Re = H), ethyl acrylate (Y = COOEt) and Pd(dppf)Cl2 resulted in the formation of a mixture of the starting material together with the cycloaddition product in a 3 1 ratio (Scheme 15). On the contrary, when Pd(OAc)2 was used in combination with the bulky phosphine ligand 2-(di-t-butylphosphino)biphenyl [41-44], the Heck reaction product was obtained as the sole product. When a mixture of the pyrazinone (Re = Ar) with ethyl acrylate or styrene and Pd(dppf)Cl2 was irradiated at 150 °C for 15 min, both catalytic systems favored the Heck reaction product with no trace of Diels-Alder adduct. 

The use of chiral bis(oxazoline) copper catalysts has also been often reported as an efficient and economic way to perform asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imines with conjugated dienes [81], with the main focus on the application of this methodology towards the preparation of biologically valuable synthons [82]. Only some representative examples are listed below. For example, the copper complex 54 (Scheme 26) has been successfully involved in the catalytic hetero Diels-Alder reaction of a substituted cyclohexadiene with ethyl glyoxylate [83], a key step in the total synthesis of (i )-dihydroactinidiolide (Scheme 30). 

In a related reaction, the Danishefsky diene 1434 cyclizes with ethyl pyruvate 1435 in the presence of catalytic amounts of the asymmetric Lewis acid catalyst 1436, at -72 °C in THF, to give the Diels-Alder adduct 1437, in 85% yield and 91% ee, and the ring-opened product 1438, which cyclizes, however, with triflic acid to give 1437 [11] (Scheme 9.9). 

Antioxidant capacities of common individual curcuminoids were determined in vitro by phosphomolybdenum and linoleic acid peroxidation methods. Antioxidant capacities expressed as ascorbic acid equivalents (pmol/g) were 3099 for curcumin, 2833 for demethoxycurcumin, and 2677 for bisdemethoxycurcumin at concentrations of 50 ppm. The same order of antioxidant activity (curcumin > demethoxycurcumin > bisdemethoxycurcumin) was observed when compared with BHT (buty-lated hydroxyl toluene) in linoleic peroxidation tests. The antioxidant activity of curcumin in the presence of ethyl linoleate was demonstrated and six reaction products were identified and structurally characterized. The mechanism proposed for this activity consisted of an oxidative coupling reaction at the 3 position of the curcumin with the lipid and a subsequent intramolecular Diels-Alder reaction. ... 

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... 

Although the metathesis of ene-ynes is a valuable method for the preparation of 1,3-butadienes, and may be used for Diels-Alder reactions, a problem arises from the need to employ either a high temperature or a Lewis add to accelerate the cycloaddition, which is usually not feasible with the Grubbs catalyst Therefore, the combination of metathesis and cycloaddition is usually performed in sequential fashion (as just shown, and highlighted earlier) [264]. However, Laschat and coworkers [265] have shown the Lewis acid BC13 to be compatible with the Grubbs I catalyst (6/3-13). Reaction of 6/3-92 and ethyl acrylate using a mixture of 2.5 equiv. of the Lewis acid and 10 mol% of 6/3-13 led to 6/3-93 in 60% yield (Scheme 6/3.27). 

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... 

A similar use of maleimide was seen in Yu s hetero-Diels-Alder reactions. The Ar-ethyl pyrazole reacted under aqueous conditions at room temperature, with air oxidation to furnish the fully aromatized product <2001TL8931>. Other 1,3-substituted pyrazoles required heating in acetic acid at 50°C for 24h, with product yields of 42-67%. 

An elegant approach toward formation of the central tetrahydropyrimidine ring has been reported by Tamura and co-workers who utilized an aza-Diels-Alder cyclization of ethyl ( )-3-aza-3-(l,3-benzoxazol-2-yl)propenoate 266 with a range of cinnamyl alcohols 267 catalyzed by l,l,3,3-tetra- -butyl-l,3-diisothiocyanatodistannoxane, and subsequent lactonization to generate the tricyclic core structure 268 (Scheme 18) <1998J(P1)3389>. 

The pyranocoumarin 105 can be prepared via a three-component Diels-Alder reaction between 4-hydroxycoumarin, ethyl vinyl ether and an a-dicarbonyl compound. Similarly to the above, upon treatment of 105 with sulfuric acid in THF, hydrolysis and rearrangement occur to give the furofurochromenone 106. The hemiacetal functionality in 106 may then be oxidized with pyridinium chlorochromate (PCC) to give the lactone 107 <2001EJ03711> (Scheme 28). 

Diels-Alder reaction, of acrolein with B-butyl cyclohexenyl ether, n-butyl vinyl ether, and ethyl isopropenyl ether, 34, 30... 

---