Crotonaldehydes Diels-Alder reaction

Diels-Alder reactions Neutral ionic liquids have been found to be excellent solvents for the Diels-Alder reaction. The first example of a Diels-Alder reaction in an ionic liquid was the reaction of methyl acrylate with cyclopentadiene in [EtNH3][N03] [40], in which significant rate enhancement was observed. Howarth et al. investigated the role of chiral imidazolium chloride and trifluoroacetate salts (dissolved in dichloromethane) in the Diels-Alder reactions between cyclopentadiene and either crotonaldehyde or methacroline [41]. It should be noted that this paper describes one of the first examples of a chiral cationic ionic liquid being used in synthesis (Scheme 5.1-17). The enantioselectivity was found to be < 5 % in this reaction for both the endo (10 %) and the exo (90 %) isomers. 

Supported Lewis acids are an interesting class of catalysts because of their operational simplicity, filterability and reusability. The polymer-bound iron Lewis-acid 53 (Figure 3.8) has been found [52] to be active in the cycloadditions of a, S-unsaturated aldehydes with several dienes. It has been prepared from (ri -vinylcyclopentadienyl)dicarbonylmethyliron which was copolymerized with divinylbenzene and then treated with trimethylsilyltriflate followed by THF. Some results of the Diels-Alder reactions of acrolein and crotonaldehyde with isoprene (2) and 2,3-dimethylbutadiene (4) are summarized in Equation 3.13. 

A recent patent describes the synthesis and catalytic use of Al-containing TUD-1 materials. Some of the reactions demonstrated inclnde hydrogenation of mesitylene (Pt as active metal) and dehydration of 1-phenyl-ethanol to styrene. Several other conceptnal reactions were also described, amongst others the Diels-Alder reaction of crotonaldehyde and dicyclopentadiene and the amination of phenol with ammonia. 

The salts were investigated in the Diels-Alder reaction of crotonaldehyde with cyclopentadiene (Scheme 67). The yields obtained were between 35% and 40% with an endo. exo ratio of 90 10. The control reaction without the salt at -25 °C gave no product. The observed ee with the enantiopure salt 66 was less than 5%. Nevertheless, this was the first example which showed, that imidazolium-based ionic liquids can be used in substoichiometric amounts as Lewis acid catalysts. 

Cycloadditions with enol ethers The Diels-Alder reaction of vinyl ethers with a,(3-unsaturated aldehydes proceeds at room temperature when catalyzed by the related lanthanide Yb(fod),. An example is the reaction of crotonaldehyde with ethyl vinyl ether (equation I). 

The boron-substituent-dependent enantioselectivity of CAB-catalyzed Diels-Alder reactions has been studied as a first step toward obtaining mechanistic information on the sp -sp conformational preferences in a, d-enals, where the possibility of s-cis or s-trans conformers exists in the transition-state assembly of Diels-Alder reaction catalyzed by Lewis acid [12]. a-Substituted a,P-ena s (e.g. methacrolein) favors an s-trans conformation in the transition-state assembly irrespective of the steric features of the boron substituent. On the other hand, the sp -sp conformational preference of a-unsubstituted a,/3-enals (acrolein and crotonaldehyde) can be reversed by altering the structure of the boron substituent an s-trans conformation is preferred when the substituent on the boron is small (H, C=CBu), whereas an s-cis conformation is preferred when the substituent is bulky (o-PhOC(jH4). 

We have also studied the solution conformations of CAB-complexed methacrolein and crotonaldehyde by use of NOE measurements (Table 1) [12]. These results are in agreement with the transition-state preference for the s-trans or s-cis conformation of a,/8-enals, on the basis of the enantioselectivity of the aldol and Diels-Alder reactions catalyzed by CAB. Finally, it has been established that the effective shielding of the si face of the CAB-coordinated a, -enal arises from /r-stacking of the 2,6-diisopropoxy-benzene ring and the coordinated aldehyde. 

The possibility that metallocenes might function as Lewis acids in Diels-Alder reactions was probed with ferrocenium hexafluorophosphate [184]. The answer is affirmative the cycloadditions studied include methacrolein, crotonaldehyde, and methyl vinyl ketone as dienophiles and butadienes and cyclopentadienes as diene components. Yields are in the range 60-80 % with reaction times of 3-36 h at 0 to 20 °C. Fair to good yields were also obtained in reactions of isoprene and cyclopentadiene with acrolein and methyl vinyl ketone in the presence of 1 % [Pd(PPh3)2(MeCN)2](BF4)2 (in CH2CI2, room temperature). Methyl acrylate resulted in low yields, and chiral modification with (5)-BINAP is reported to give the cycloadducts with modest enantioselectivity [164]. 

Diels-Alder reactions of cyclopentadiene and methacrolein with crotonaldehyde are also catalyzed by complexes formed in situ between NbCls or TaCls and bidentate ligands (2 equiv.) such as L-tartrate esters, or a-amino acids (e.g. tryptophan, alanine). Yields with the Ta catalysts are often somewhat better (14-78 %) than with the Nb catalysts. Good exo. endo ratios are obtained but enantioselectivities are still low (7-40 % ee) [185]. Methylrhenium trioxide is an efficient catalyst in these reactions and its best performance is in aqueous solution. Acrolein derivatives and methyl vinyl ketones react with a variety of dienes to give single diastereoisomers in very high yield with as little as 1 % catalyst loading [186]. Examples are shown in Sch. 49. The reaction is sluggish with disubstituted dienophiles and dienes. 

In the course of their application to the natural product, Danishefsky provided a total synthesis of (+ )-lincosamine (Scheme 30) (83JA6715 85JA1274). An intermolecular hetero Diels-Alder reaction of the diene mixture 195 with crotonaldehyde (210) under the influence of trifluoroacetic acid at -78°C gave a 67% yield of the 2-[( )-l-propenyl]pyrone 211. Reduction of the ketone 211 by Luche s procedure (79JA5848) followed by benzoylation afforded the galactal derivative 212. Treatment of 212 with m-chloroperbenzoic acid in anhydrous methanol followed by benzoylation afforded the methyl galactoside 213. Reaction of 213 with N-bromosuccin-imide in the presence of wet acetic acid produced a single bromohydrin (214). 

Diels-Alder reactions At -78° in ether, the NbClj-catalyzed cycloaddition between cyclopentadiene and crotonaldehyde is complete in 1 h. Interestingly, the endo-to-exo ratio is 1 9. 

Diels-Alder reaction. The Diels-Alder reaction of 1 with franj-crotonaldehyde... 

High ees in the Diels-Alder cycloaddition of cyclopentadiene (8.06) and a range of enals (8.95) are obtained using (8.91), and similar levels of enantioselectiv-ity are seen in the reaction of acrolein (8.63) and crotonaldehyde (8.99) with a variety of simple dienes such as (8.98). The related catalyst (8.101) has been applied with success to the intramolecular Diels-Alder reaction. For instance the trienal (8.102) undergoes cycloaddition, in the presence of this catalyst, to give decalin (8.103), which was converted in four further steps to the marine natural... 

MacMillan s imidazolidinone salts, used successfully in the organocatalysed Diels-Alder reaction (see Section 8.1) also function as effective catalysts in the asymmetric nitrone cycloaddition with simple monodentate dipolarophiles. Thus acrolein (8.63) and crotonaldehyde (8.99) both react with acyclic C-aryl, N-benzyl nitrones and C-aryl N-alkyl nitrones such as (8.198) with high ees ranging from 90 to 99% in the presence of the perchlorate salt of imidazolidinone (8.91). 

Diels-Alder reaction of crotonaldehyde and dicyclopentadiene Amination of phenol with ammonia Hydrotreating of FCC clarified slurry oil... 

The HOMO activation of dienophiles (reversed electron demand DA) was reported by Chen and co-workers [32]. They found that the catalytic reaction of crotonaldehyde with prolinol ether 46 resulted in formation of a 1,3-dieneamine 49 that selectively reacted as a dienophile on the terminal double bond in a reversed electron demand Diels-Alder reaction with electron-deficient dienes 48 to give access to highly diastereo- and enantioenriched cyclohexen derivatives 50 (Scheme 6.12). 

The CAB process is quite general for simple dienes and aldehydes. The a-sub-stituent on the dienophile increases the enantioselectivity (acrolein vs methacrolein). When there is a P-substitution in the dienophile, as in crotonaldehyde, the cycloadduct is nearly racemic. Conversely, for a substrate with substituents at both a-and P-positions, high ees are observed, as with 2-methylcrotonaldehyde and cy-clopentadiene (90% ee, exo endo = 97 3). a-Bromoacrolein is a useful dienophile in the Diels-Alder process because of the exceptional synthetic versatility of its resulting adducts e.g., an important intermediate for prostaglandin synthesis [19a]. In the presence of 10 mol% of 3a, a-bromoacrolein and cyclopentadiene in dichloro-methane undergo a smooth Diels-Alder reaction to give the (S)-bromoaldehyde cycloadduct in quantitative yield, 95% ee and 94 6 (exo endo CHO) diastereoselectivity (Equation 20). Similar results are obtained for the catalyst 3b in propionitrile. Other examples are listed below [20]. 

In 1991, Hossain and coworker [8] reported that Fe transition-metal Lewis acid, [CpFe+(CO)P(OCH3)3(THF)]BF4 (26b) was found to be an effective catalyst of Diels-Alder reactions of several diene with crotonaldehyde and acrolein with good yield of cycloaddition products (Scheme 16.6). 

Although commercially available, 1-trimethylsilyloxy-1,3-butadiene (1) can be easily prepared by silylation of crotonaldehyde. It has often been used as a reactive diene in Diels-Alder reactions. For example, reaction with dimethyl acetylenedicarboxylate (2) affords the cyclohexadiene diester (3) in 68% yield. This initial Diels-Alder adduct can be converted into two different aromatic products by the proper choice of conditions namely, thermal elimination affords the phthalate (4), while oxidation produces the phenol (5), hoth in good yield (eq 1). Reaction with methyl 3-nitroacrylate (6) followed hy hydrolysis of the initial adduct (7) and elimination of the -nitro group leads to the cyclohexadienol (8) (eq 2). Many other Diels-Alder reactions of this type have been carried out using (1), as shown in Table 1. In general, the endo adduct is favored, especially at lower temperatures. 

The pumiliotoxins are a group of more than 60 alkaloids isolated from the toxic skin secretions of the frog Dendrobates pumilis and related species. Many of the alkaloids have, as a central feature, the unusual c/s-decahydroquinoline structure, and since they possess interesting neurological activities they are an attractive target for total synthesis. A new total synthesis of rf,/-pumiliotoxin C has been reported. The main feature of the new synthesis is the Diels-Alder reaction of an activated N-acylaminodiene and a crotonaldehyde derivative leading to an intermediate with two chiral centres which can be utilized to control the introduction of the third chiral centre (Scheme 67). The method, which is short and efficient, should be useful in the synthesis of other cis-decahydroquinoline alkaloids. The overall yield of c/,/-pumiliotoxin C was 51%. 

Asymmetric inverse-electron-demand Diels-Alder reactions controlled by the dienophile HOMO and the diene LUMO have seldom been reported. Through a HOMO-activation strategy by the formation of dienamine intermediate H between crotonaldehyde (2a) and chiral amine 36 to raise the dienophile HOMO energy, Chen and coworkers successfully developed the first organocatalytic aU-carbon-based inverse-electron-demand Diels-Alder reaction to produce multifunctional cycloadducts 35 with up to 99% ee (Scheme 38.11) [19]. 

Although the diversity of asymmetric inverse-electron-demand hetero-Diels-Alder reactions has been weU established, examples of aU-carbon-based catalytic asymmetric versions have rarely been reported, and aU faU into the LUMO-lowering strategy. Based on previous applications of dienamine catalysis in asymmetric inverse-electron-demand hetero-Diels-Alder reactions, Li et al. extended this strategy to all-carbon-based asymmetric inverse-electron-demand Diels-Alder reactions (Scheme 1.28) [36]. The products of cyclohexene derivatives with substantial substitution diversity of electron-deficient dienes and crotonaldehyde were obtained with high diastereo- and enantioselectivities (up to 99% ee, dr up to 95 5). 

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