Aromatic hetero Diels-Alder reaction

The following example is a sequence consisting of a Knoevenagel condensation and a subsequent hetero-Diels-Alder reaction. An aromatic... 

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. 

Scheme 2.164. Domino Knoevenagel/hetero-Diels-Alder reaction with aromatic aldehydes...

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%. 

The asymmetric hetero-Diels-Alder reaction of aldehydes with Danishefsky s diene catalyzed by Ti catalysts generated from a library of 13 chiral ligands or activators has also been reported (Scheme 8.18). The catalyst library contains 104 members. The Ti catalysts bearing L, L , L, and J are found to have a remarkable effect on both enantioselectivity (76.7-95.7% ee) and yield (63-100%). On the other hand, ligands bearing sterically demanding substituents at the 3,3 -positions are found to be detrimental to the reaction. The optimized catalysts, both L /Ti/L and L /Ti/L , are the most efficient for the reaction of a variety of aldehydes, including aromatic, olefinic, and aliphatic derivatives. 

Indian workers described the synthesis of l,3,4-thiadiazolo[3,2-a]-5-triazine-5(//)-thiones (61) by a hetero Diels-Alder reaction between 2-(arylideneamino)-5-ethylthio-l,3,4-thiadiazoles (60) and aromatic isothiocyanates (Equation (2)) <94MI 410-0I>. Thiadiazoles can be reduced with sodium amalgam to the aldehyde thiosemicarbazone while lithium aluminum hydride will reduce mesoionic thiadiazoles all the way to the hydrazine <84CHEC-I(4)545>. 

Bismuth(lll) chloride catalyzes the intramolecular hetero-Diels-Alder reaction of aldimines, generated in situ from aromatic amines and the A -allyl derivative of o-aminobenzaldehyde, in acetonitrile at reflux to generate [l,6]naphthyridine derivatives <2002TL1573>. The hetero-Diels-Alder reaction of 3-aryl-2-benzoyl-2-propeneni-triles and enol ethers yields 2-alkoxy, 6-diaryl-3,4-dihydro-2//-pyran-5-carbonitriles (Scheme 29) <1997M1157>. 

A low amount (1 mol%) of triflic acid is sufficient to carry out the hetero Diels-Alder reaction of aromatic aldehydes with simple dienes to furnish 3,6-dihyro-2/7-pyran derivatives in moderate to good yields692 [Eq. (5.248)]. The strongly deactivated para-methoxybenzaldehyde and pentanal gave the products in very low yields. 

Vankar and co-workers709 have shown that Nafion-H can catalyze the hetero Diels-Alder reaction between the Danisefsky diene 164 and aromatic imines to form 2,3-dihydro-y-pyridones (Scheme 5.69). The reaction with aromatic aldehydes, however, yields only the Mukaiyama aldol condensation products. 

Inanaga et al. have reported the preparation of the new chiral Yb(III) phosphate complex 180 (Figure 43), which is an efficient catalyst for asymmetric hetero-Diels-Alder reactions of 181 with aromatic aldehydes and/or a,P-unsaturated aldehydes. 2,6-Lutidine is found to be an effective additive to obtain high enantioselectivities.98 Another asymmetric catalysis for hetero-Diels-Alder reaction was reported by Mikami et al.99 An illustrative example is shown in Figure 44, wherein the interesting effects of water as an additive were observed to increase not only the enantioselectivity but also the chemical yield. 

The domino reaction consists of a Knoevenagel condensation giving an intermediate that immediately undergoes an intramolecular hetero-Diels-Alder reaction with inverse electron demand [31]. As aldehydes, rac-dtronellal, an aromatic aldehyde, and two commercially available 1,3-diketones, 1,3-dimethylbarbituric add and Meldrum s acid, were seleded. By combinations of these reactants, different cycloadducts were generated. 

A six-membered ring with two new cr bonds in a 1,3-relationship may indicate a [4 + 2] cycloaddition (Diels-Alder or hetero-Diels-Alder reaction). When the new ring is fused to an aromatic one, benzyne or an o-xylylene may have been a reactive intermediate. 

One sure way to make the hetero Diels-Alder reaction go well and with regio-and stereoselectivity is to make it intramolecular.14 The highly reactive diene 90 is formed by elimination with fluoride ion from 89. The cycloaddition is rapid because it restores aromaticity. The regiose-lectivity is as expected from HOMO of dienophile plus LUMO of diene but is probably controlled by the tether.15 The stereochemistry certainly is the azadiene is attached to the bottom face of the five-membered ring and is delivered to the bottom face of the dienophile to give the all-trans aza-oestrone 91. 

Although it is a stoichiometric procedure, the intramolecular hetero-Diels-Alder reaction of l-oxa-l,3-butadienes, obtained in situ by a Knoevenagel condensation of aromatic aldehydes and N,N -dimethylbarbituric acid, is mediated by a chiral titanium Lewis acid 29 which has l,2 5,6-di-0-isopropylidene-a-D-glucofuranose as a ligand. The highest ee-value was obtained in the reaction of 30 with 31 in isodurene as illustrated in Scheme 13[26]. 

Mikami and coworkers also reported the development of lanthanide bis(trif-luoromethanesulfonyl)amides (bistrifylamides) as a new type of asymmetric catalysts for the hetero-Diels-Alder reaction of Danishefsky s diene, wherein the significant effect of water as an additive is observed in increasing not only the enan-tioselectivity but also the chemical yield. Bistrifylamides can be used as effective bidentate Hgands to increase the Lewis acidity of their chiral metal complexes on account of the higher acidity of the conjugated acids than those of afiphatic and aromatic diols, which are commonly used as chiral bidentate hgands [33]. 

Double intramolecular hetero-Diels-Alder reaction of 1,3-diynil-bis-a,/(-unsaturated hydrazones 139 and 140 is a good example of a thermal multiple Diels-Alder reaction and is a particularly attractive route to annelated pyridines [123]. The initial cycloadduct readily aromatizes by the loss of dimethylamine (Scheme 2.52) under thermal reaction conditions. 

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