Coumarins Diels—Alder reaction

The reaction of o-iodophenol, norbornadiene and CO proceeds via alkene and CO insertions to afford the lactone 562, which is converted into coumarin (563) by the retro-Diels-Alder reaction. In this coumarin synthesis, norbona-diene behaves as a masked acetylene[4)3],... 

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-... 

The Pechmann and Knoevenagel reactions have been widely used to synthesise coumarins and developments in both have been reported. Activated phenols react rapidly with ethyl acetoacetate, propenoic acid and propynoic acid under microwave irradiation using cation-exchange resins as catalyst <99SL608>. Similarly, salicylaldehydes are converted into coumarin-3-carboxylic acids when the reaction with malonic acid is catalysed by the montmorillonite KSF <99JOC1033>. In both cases the use of a solid catalyst has environmentally friendly benefits. Methyl 3-(3-coumarinyl)propenoate 44, prepared from dimethyl glutaconate and salicylaldehyde, is a stable electron deficient diene which reacts with enamines to form benzo[c]coumarins. An inverse electron demand Diels-Alder reaction is followed by elimination of a secondary amine and aromatisation (Scheme 26) <99SL477>. 

The hyperbaric 4 + 2-cycloaddition of 1,2,4-trioxegenated 1,3-dienes with dieno-philes, A-phenylmaleimide, and methyl and phenyl acrylates produced the expected endo-cycloadducts with excellent stereo- and regio-control.113 The high-pressure (g) Diels-Alder reactions of 3-substituted coumarins with methylbuta-1,3-dienes in water formed tetrahydro-6H-benzo[c]chromen-6-ones in high yields (85-95%).114... 

The use of coumarin in Diels-Alder reactions is, by comparison to pyran-2-ones, still largely unexplored. This is likely due to the low reactivity of the double bond at positions 3 and 4. Diels-Alder reactions with 3-substituted coumarins are rare, despite the potential to synthesize tetrahydro-6//-benzo[c]chromen-6-ones, important precursors to functionalized biphenyls and several natural products. Electron-withdrawing substitution at C-3 does not serve to efficiently activate the dienophilic system thus, it has been found that high temperatures and pressures are necessary to effect the reaction (e.g., Equation 25) <2006JOC70>. 

It is also worth mentioning that inverse electron demand Diels-Alder reactions are possible with pyran-2-ones and coumarins. Shown in Equation (26) is one such reaction using an electron-deficient diene of coumarin 258 with enamine 259 to give 260 <1999SL477>. 

Iodophenol has been carbonylated in the presence of norbornadiene to give a reasonable yield of coumarin, which is formed by a spontaneous retro Diels-Alder reaction from the initially formed product (equation 158)891. 

The enol form of dihydrofuro[2,3-, ]coumarin-9-one 116 was also employed as a dienophile in the Diels-Alder reaction with 3,6-bis(trifluoromethyl)l,2,4,5-tetrazine 117 to afford the desired tetracyclic product 118 in 54% yield (Equation 104) <2002S43>. 

We have been particularly enamored with the development of experiments involving carbon-carbon bond formation, especially as part of tandem reactions occurring in a single container (see the Diels-Alder reaction. Figure 1). One such reaction is the synthesis of simple esters of coumarin-3-carboxylic acids via a Knoevenagel condensation between malonic esters and various a-hydroxybenzaldehydes, followed by intramolecular nucleophilic acyl substitution. This conversion, catalyzed by piperidine, has been carried out under a variety of conditions, for example, at room temperature without solvent... 

Diels-Alder-based strategy (Scheme 18).90 An analogous route has also been explored by Miller et a/.91 who obtained the acetoxy-aldehyde (152) from the Diels-Alder reaction of 3-methylbuta-l,3-dienyl acetate with 2-methylprop-2-enal. Cyclization of (152) with sodium hydride gave the coumarin derivative (153). Unfortunately, cyclization of the corresponding methyl ketone (154) yielded the chromanone derivative (155) and not the methyl analogue of (153). 

Coumarins, but not apparently chromones, serve as dienophiles in Diels-Alder reactions, though under relatively forcing conditions " in water such additions take place at 150 °C and under high pressure, at... 

Inverse demand Diels-Alder reactions of tetrazines 1 to psoralenes 267 were reported to furnish tetracyclic pyridazine dicarboxylates 268, which were used as the key intermediates in the synthesis of nitrogenated isosteres of potent DNA inhibitors <2003T8171>. In some cases, cycloaddition was followed by opening of the furan ring to give pyridazinyl-substituted coumarins 271 (Scheme 66) <2000JHC907, 2003SL2225>. 

Scheme 5.2-76 The Knoevenagel hetero-Diels-Alder reaction coumarin synthesis [186].

Certain plants of the Rutaceae produce a number of different coumarin dimers in which the monomeric units, an isopentadienyl-substituted coumarin, are joined in a Diels-Alder fashion. The structural features resulting from this mode of dimerization are not restricted to coumarins in the Rutaceae but can also be found in two sets of dimeric 2-quinolones, indole alkaloids and related isopentenyl substituted compounds. A remarkable feature of all of these dimers is that they occur as racemates in spite of the fact that they all have two or more asymmetric centers. The racemic nature of these coumarin dimers has raised the possibility that these substances might arise by a non-enzymatic Diels-Alder reaction during biosynthesis. 

The carbonylative cyclization of 2-iodophenols with norbornadiene or norbornene was also carried out. In 1989, Catellani s group studied the annulation of 2-iodophenol with norbornadiene to coumarin (Scheme 3.11a). ° In this method, the elimination of cyclopentadiene via retro-Diels-Alder reaction was involved in the formation of the terminal product. Fiaud and co-workers reported the palladium-catalyzed carbonylative cyclization of 2-iodophenol with norbornene in 1997 (Scheme 3.11b). They reported that the selectivity for the production of the two regioisomers can be controlled. Catellani and co-workers studied the intramolecular cyclization of ort/zo-iodophenyl 3-butenoate to 4-methylcoumarin with a palladium catalyst. 85% of 4-methylcoumarin was produced in the presence of benzonitrile and carbon monoxide, which is compulsory (Scheme 3.12a). Silva, Costa and their co-workers reported a tandem process for the synthesis of coumarins from 2-iodophenols and enoates with the assistance of a palladium catalyst (Scheme 3.12b). The general scope of this Heck-lactonization involves E- and Z-enoates as substrates. It was shown that this reaction is sensitive to steric hindrance around the double bound in... 

There are many well-studied photochemical reactions that are clean, high yielding, relatively fast, and require no chemical catalysts. A number of these have been examined for SCNP formation, including the photochemically triggered Diels-Alder reaction between 2,5-dimethylbenzophenone and maleimide, the photo-dimerization of coumarin, the photodimerization of anthracene, and the photo-induced nitrile imine mediated tetrazole-ene cycloaddition. ... 

The usefulness of Hf catalyst for the Diels-Alder reaction was also applied for the reaction of coumarin (111) with isoprene (Equation 51) [56]. Interestingly, the reaction could be performed under solvent-free conditions, and afforded tricyclic compound (112) in excellent yield when the tetrahydrofuran (THE) complex of HfCU was employed for the reaction, whereas Hf(OTf)4 or HfCU itself showed much less activity. 

There was no reaction between 199a and dienes 197 under atmospheric pressure, at low temperature (55 °C) and for long period of time (72h). A moderate conversion was obtained by heating for 48h 199a with dienes 197 in toluene at 110 °C (Table 3). These results clearly demonstrate the advantage of HP conditions to accelerate the Diels-Alder reaction. Application of best reaction conditions to the series of coumarins 199b-g afforded a series of substituted 6a-cyano-tetrahydro-6H-benzo[c]chromen-6-ones (Table 4). 

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