Diels-Alder reactions butadienes with aldehydes

Danshefsky s diene [19] is the 1,3-butadiene with amethoxy group at the 1-position and a trimethylsiloxy group at the 3-position (Scheme 18). This diene and Lewis acids extended the scope of hetereo-Diels-Alder reactions with aldehydes [20], This diene reacts with virtually any aldehyde in the presence of Lewis acids whereas dienes usually react with only selected aldehydes bearing strongly electron accepting a-substituents. There are two (Diels-Alder and Mukaiyama aldol) reaction pathways (Scheme 18) identified for the Lewis acids catalyzed reactions of Danishefsky diene with aldehydes [21, 22]. The two pathways suggest that these reactions occur on the boundary between the delocahzation band (the pericyclic... 

Diels-Alder reactions with aldehydes.2 This catalyst is superior to zinc chloride3 for promoting [4 + 2]cycloaddition of aldehydes with l-alkoxy-3-trimethylsilyloxy-1,3-butadienes to form 2,3-dihydro-4//-pyrane-4-ones. The catalyst prepared from bornyl alcohol is somewhat more effective than similar catalysts from simple alcohols, and may be of value for asymmetric induction. 

In the Diels-Alder reaction with inverse electron demand, the overlap of the LUMO of the 1-oxa-l,3-butadiene with the HOMO of the dienophile is dominant. Since the electron-withdrawing group at the oxabutadiene at the 3-position lowers its LUMO dramatically, the cycloaddition as well as the condensation usually take place at room or slightly elevated temperature. There is actually no restriction for the aldehydes. Thus, aromatic, heteroaromatic, saturated aliphatic and unsaturated aliphatic aldehydes may be used. For example, a-oxocarbocylic esters or 1,2-dike-tones for instance have been employed as ketones. Furthermore, 1,3-dicarbonyl compounds cyclic and acyclic substances such as Meldmm s acid, barbituric acid and derivates, coumarins, any type of cycloalkane-1,3-dione, (1-ketoesters, and 1,3-diones as well as their phosphorus, nitrogen and sulfur analogues, can also be ap-... 

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]. 

Diels-Alder reactions with electron-rich alkenes.1 Simple a,(i-unsaturated im-ines (1-aza-1,3-butadienes) do not undergo Diels-Alder reactions with dienophiles. In contrast, the N-phenylsulfonyl imines derived from an aldehyde or ketone undergo Diels-Alder reactions under forcing conditions with electron-rich dienophiles to... 

Thus, Ghosez et al. were successful in showing that A,iV-dimethyl hydrazones prepared from a,/3-unsaturated aldehydes react smoothly in normal electron demand Diels-Alder reactions with electron-deficient dienophiles [218, 219]. Most of the more recent applications of such 1-aza-l,3-butadienes are directed towards the synthesis of biologically active aromatic alkaloids and azaanthra-quinones [220-224] a current example is the preparation of eupomatidine alkaloids recently published by Kubo and his coworkers. The tricyclic adduct 3-19 resulting from cycloaddition of naphthoquinone 3-17 and hydrazone 3-18 was easily transformed to eupomatidine-2 3-20 (Fig. 3-6) [225]. 

Simple a,3-unsaturated aldehydes, ketones, and esters (R = C02Me H > alkyl, aryl OR equation l)i, 60 preferentially participate in LUMOdiene-controlled Diels-Alder reactions with electron-rich, strained, and selected simple alkene and alkyne dienophiles, - although the thermal reaction conditions required are relatively harsh (150-250 C) and the reactions are characterized by the competitive dimerization and polymerization of the 1-oxa-1,3-butadiene. Typical dienophiles have included enol ethers, thioenol ethers, alkynyl ethers, ketene acetals, enamines, ynamines, ketene aminals, and selected simple alkenes representative examples are detailed in Table 2. - The most extensively studied reaction in the series is the [4 + 2] cycloaddition reaction of a,3-unsaturated ketones with enol ethers and E)esimoni,... 

The domino Knoevenagel condensation hetero-Diels-Alder reaction was used for the enantioselective total synthesis of the active anti-influenza A virus indole alkaloid hirsutine and related compounds by L.F. Tietze and co-workers. The Knoevenagel condensation was carried out between an enantiopure aldehyde and Meldrum s acid in the presence of ethyienediamine diacetate. The resulting highly reactive 1-oxa-1,3-butadiene underwent a hetero-Diels-Alder reaction with 4-methoxybenzyi butenyl ether ElZ = 1 1) in situ. The product exhibited a 1,3-asymmetric induction greater than 20 1. 

Cycloaddition reactions are not only used to construct quinoline derivatives, but also used to elaborate them. Phenanthridone derivatives were prepared by Diels-Alder reactions with 2(l )-quinolones and butadiene derivatives <01CPB407>. The synthesis of pyranoquinolines via a formal [3 + 3] cycloaddition was also reported. For example, aldehyde 66 was treated with piperidine and acetic anhydride to afford the corresponding iminum ion which undergoes a [3 + 3] cycloaddition with 4-hydroxyquinolone (67) to give pyranoquinoline 68. Intermediates such as pyranoquinoline 68 were used in the total syntheses of simulenoline and huajiaosimuline <01JOC1049>. 

Encouraged by Jprgensen s inverse-electron-demand hetero-Diels-Alder reaction of aldehydes and a,P-unsaturated a-keto esters, Han, He, and others envisaged that an unprecedented asymmetric aza-Diels-Alder reaction of A-sulfonyl-l-aza-1,3-butadienes and aldehydes might be developed by employing a similar strategy. They found that the process proceeded with a chiral secondary amine, 34 (Scheme 1.26) [32]. Excellent enantioselectivities (up to 99% ee) were observed for a broad spectrum of substrates under mild conditions. 

The aldehyde group in tricarbonyl(Ti -2,4-hexadien-l-al)iron can undergo a hetero-Diels-Alder reaction with l-methoxy-3-trimethylsilyloxy-1,3-butadiene to give di-hydropyranones with moderate diastereoselectivity depending on the Lewis acid applied. ... 

Catalysis of Diels-Alder Reactions. EtAlCb is a useful Lewis acid catalyst for Diels-Alder reactions. It is reported to be more efficacious for the Diels-Alder reaction of Acrolein and butadiene than either AICI3 or Et2AlCl. It is a useful catalyst for intramolecular Diels-Alder reactions with a,p-unsaturated esters (eq 4) and aldehydes as dienophiles. It has also proven to be a very efficient catalyst for the inter- and intramolecular asymmetric Diels-Alder reaction of chiral a,p-unsaturated acyl sultams (eq 5) and has been used to catalyze a wide variety of Diels-Alder... 

The influence of alkyl substituents on the asynchronous transition-state structure of the BF3-catalyzed carbo-Diels-Alder reaction of a,/ -unsaturated aldehydes with 1,1-dimethyl-l,3-butadiene derivatives has been investigated by Dai et al. [13]. 

Simple imines are poor dienophiles and must be activated by protonation or by attaching an electron-withdrawing group to the nitrogen atom. Scheme 6.10 illustrates the Diels-Alder reactions of benzyliminium ion 25, generated in situ from an aqueous solution of benzylamine hydrochloride and commercial aqueous formaldehyde, with methylsubstituted 1,3-butadienes [22]. This aqueous Diels-Alder reaction combines three components (an aldehyde, an amine... 

The aqueous aza-Diels-Alder reaction of an aldehyde and an amine hydrochloride with a diene is catalyzed by lanthanide(III) trifluoromethane sulfonates (Ln(OTf)3, triflates [24]). Some examples are reported in Schemes 6.12 and 6.13. With respect to uncatalyzed reactions, the lanthanide catalyst allows milder reaction conditions, increases the reaction yield and does not affect the diaster-eoselectivity of the reaction, but influences the regiochemistry as in the cycloaddition of 25 with 1,3-dimethyl-1,3-butadiene (Schemes 6.10 and 6.12). These results have been applied [24b-d] to the synthesis of azasugars (Scheme 6.14). 

Optically active /3-ketoiminato cobalt(III) compounds based on chiral substituted ethylenedi-amine find use as efficient catalysts for the enatioselective hetero Diels Alder reaction of both aryl and alkyl aldehydes with l-methoxy-(3-(t-butyldimethylsilyl)oxy)-1,3-butadiene.1381 Cobalt(II) compounds of the same class of ligands promote enantioselective borohydride reduction of ketones, imines, and a,/3-unsaturated carboxylates.1382... 

It can be assumed that, in the presence of InCl3 and water, the cyclic enol ethers 2-618 form a hydroxy aldehyde which reacts with the aniline to give an aromatic im-inium ion. This represents an electron-poor 1,3-butadiene which can undergo a hetero-Diels-Alder reaction [323] with another molecule of 2-618 to give a mixture of the diastereomeric tetrahydroquinolines 2-619 and 2-620. 

So far, only those domino Knoevenagel/hetero-Diels-Alder reactions have been discussed where the cycloaddition takes place at an intramolecular mode however, the reaction can also be performed as a three-component transformation by applying an intermolecular Diels-Alder reaction. In this process again as the first step a Knoevenagel reaction of an aldehyde or a ketone with a 1,3-dicarbonyl compound occurs. However, the second step is now an intermolecular hetero-Diels-Alder reaction of the formed 1 -oxa-1,3 -butadiene with a dienophile in the reaction mixture. The scope of this type of reaction, and especially the possibility of obtaining highly diversified molecules, is even higher than in the case of the two-component transformation. The stereoselectivity of the cycloaddition step is found to be less pronounced, however. 

The Hall group [52] has developed a new three-component domino reaction of 1-aza-4-borono-1,3-butadiene 4-152, a dienophile and an aldehyde to give a-hydroxy-methylpiperidine derivatives. In the first step, a hetero-Diels-Alder reaction takes place, which is followed by allylboration. As an example, reaction of 4-152 with the maleimide 4-153 in the presence of benzaldehyde furnished 4-154 in yields of up to 80% using the three substrates in a 1 2 1 ratio (Scheme 4.32). 

Because a comprehensive discussion of the transition state of hydrogen-bond catalysis will be presented by Berkessel in Chapter 3, the hydrogen bond catalyzed hetero Diels-Alder reaction of butadiene with carbonyl compounds will be discussed briefly here. Huang and Rawal reported that the hetero Diels-Alder reaction of aminodiene with aldehyde exhibited significant solvent effects (Scheme 2.7) [15]. The reaction in CHCfi was accelerated 30 times in comparison with that in THF, while that in i-PrOH was accelerated 630 times. They proposed that the Diels-Alder reaction was promoted by the hydrogen-bond activation of aldehyde. This finding resulted in the development of TADDOL catalyst [3]. 

Currently available chiral Diels-Alder catalysts have major limitations with regard to the range of dienes to which they can be applied successfully. Indeed, most of the reported catalytic enantioselective Diels-Alder reactions involve reactive dienes such as cyclopentadiene, but 1,3-butadiene and 1,3-cyclohexadiene have not been successfully utilized without reactive 2-bromoacrolein. To solve this problem, a new class of super-reactive chiral Lewis acid catalysts has been developed from chiral tertiary amino alcohols and BBr3 [24] (Eq. 8A.13). This type of chiral super Lewis acid works well for a,fj-acetylenic aldehydes [25],... 

Solid-phase three-component domino-Knoevenagel-hetero-Diels-Alder reaction can also be performed using a resin-linked 1,3-dicarbonyl compound such as 100 with aldehydes and an enol ether to give dihydropyrans 102 via the intermediately formed 1-oxa-l,3-butadiene 101 (Scheme 5.18) [30], The resin can be deaved off after the reaction by solvolysis, for instance using sodium methanolate to give the corresponding methyl ester 103 as a mixture of diastereomers. The overall yield varies from 12 to 37% and the selectivity from 1 1 to 1 5 in favor of the tis-product depending on the applied aldehyde. The crude dihydropyrans thus obtained are reasonably pure (> 90% HPLC). 

Chiral aldehydes such as N-protected a-aminoaldehydes and a-alkoxyalde-hydes as well as chiral butadienes derived from sugars by a Wittig reaction have also been used in the hetero Diels-Alder reactions successfully with the inducing stereogenic centers remaining in the obtained cycloadducts. 

Similarly, Keck [111] has used the Ti(0-i-Pr)4/BINOL complex (10 mol %) for the hetero Diels-Alder reaction of l-methoxy-3-trimethylsilyloxy-1,3-butadienes 2-10 and non-activated aldehydes. The lowest enantioselectivity was obtained with benzaldehyde and the best with phenylacetaldehyde and some aliphatic aldehydes to give the corresponding dihydropyrans with ee values ranging from 75 % up to 97%. 

A high asymmetric induction in intramolecular hetero Diels-Alder reactions was found using chiral 1-oxa-1,3-butadienes with a stereogenic center in the tether [54]. Such compounds can easily be obtained by a Knoevenagel condensation of a 1,3-dicarbonyl compound such as iV,N-dimethylbarbituric acid with a chiral aldehyde bearing a dienophile moiety [169 a] (Scheme 2-3). With the stereogenic center in a-position relative to the oxadiene or dienophile moiety an excellent induced diastereoselectivity is obtained for the nearly exclusively formed trans-cycloadduct (simple diastereoselectivity = 97.9 2.1 and 98.3 1.7,... 

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