Resorcinol, reaction with ethyl acetoacetate

Zeolites have been shown to catalyse a variety of related reactions (Downing et al., 1997), e.g. zeolite beta catalyses the synthesis of coumarins via the Pechmann condensation. For example, condensation of resorcinol with ethyl acetoacetate over zeolite beta in refluxing toluene gave methylumbelliferone, a perfumery ingredient, in 70-80% yield (Fig. 2.24) (Gunnewegh ef a/., 1996). 

Coumarins are an important family of fragrance chemicals with herbaceous, haylike odors. The conventional methods for coumarin synthesis require drastic conditions. For example, 4-methyl-7-hydroxycoumarin 39 (Eq. 15.4.1) is prepared via the Pechmann reaction by stirring a mixture of resorcinol 37 and ethyl acetoacetate 38 in H2SO4 for 12-14 h (63). 

The Pechmann synthesis of coumarins via condensation of phenols with keto esters also involves an intramolecular hydroxyalkylation, following initial transesterification, and subsequent dehydration. It was found that H-Beta could successfully replace the sulfuric acid conventionally used as catalyst. For example, reaction of resorcinol with ethyl acetoacetate afforded methylumbelliferone (Figure 11.9), a perfumery ingredient and insecticide... 

Phosphorus oxychloride (POCI3) has proven useful as a promoter in a range of Pechmann condensations employing sterically encumbered 3-keto ester coupling partners and electronically deactivated phenols, reactions which fail using sulfuric acid as a promoter. Thus POCI3 has been found to successfully promote the condensation of a-benzylacetoacetate and 1-naphthol as well as the reaction of ethyl acetoacetate with 4-acyl-resorcinols. ... 

Application of MW irradiation in the solid add-catalyzed reaction of resorcinol and phloroglucinol with ethyl acetoacetate and propenoic and propynoic acid resulted in the formation of corresponding hydroxy coumarins in very high yields, avoiding the acidic waste associated with aqueous and Lewis adds (De la Hoz et al. 1999). 

A mixture of resorcinol (550 mg, 5 mmol) and ethyl acetoacetate (650 mg, 5 mmol) was heated at 75 °C for 1 h (TLC). The reaction mixture was cooled to room temperature and poured into crushed ice (10 g). The crystalline products were collected by filtration under suction and washed with cold H20. The pure product was obtained by recrystallization from hot EtOH mp 184-186 °C. 

Another route to coumarins is the Pechmann condensation of phenols with (3-ketoesters. The reaction proceeds via transesterification and intramolecular hydroxyalkylation, followed by dehydration, and is conventionally conducted using sulfuric acid as catalyst. Resorcinol and ethyl acetoacetate reacted sol vent-free over H-beta at 150 °C to give 7-hydroxy-4-methylcoumarin (78 % isolated yield) [85J. This is another perfumery ingredient which is also an intermediate for the insecticide I Iymecromone. 

The mixture of resorcinol and ethyl acetoacetate must be added to the previously cooled cone. H2SO4 with constant stirring very gradually so that the temperature of the reaction mixture should be maintained below 10°C. 

A 5-L, three-necked round-bottomed flask fitted with a mechanical stirrer, thermometer, and dropping funnel was charged with concentrated sulfuric acid (2 L), and the flask was cooled to an internal temperature of < 10 °C on an ice bath. A solution of resorcinol (14 220 g, 2.00 mol) in freshly distilled ethyl acetoacetate (7 260 g, 2.00 mol) was then added (dropwise) to the stirred reaction, keeping the internal temperature below 10 °C. Once the addition was complete ( 2 h), the reaction mixture was allow to stand for 12-24 h without further cooling. The reaction mixture was subsequently added to a vigorously stirred mixture of ice (4 kg) and water (6 L). The precipitated solid was collected by vacuum filtration and washed with cold water (3 x 50 mL). The washed solid was then dissolved in 5% aqueous sodium hydroxide solution (3 L), the solution was filtered, and dilute sulfuric acid (1 10 cone, sulfuric acid/water 1.1 L) was slowly added to the vigorously stirred filtrate (final pH 4.5) to precipitate the coumarin product. The product was collected by vacuum filtration, washed with cold water (4 x 50 mL), and dried in vacuo to provide 4-methyl-7-hydroxycoumarin (26 290-320 g, 82-90% yield). The product could be recrystallized from 95% ethanol ( 15 mL ethanol/5 g product) to provide nearly colorless needles (mp 185 X). 

Environmentally benign synthesis routes for umbelliferone (I), 7-hydroxy-4-methylcoumarin (II), 3,4-dihydrocoumarin (III), and tricyclic coumarin (IV) (Figure 10.2) were developed using zeolite-H-p or Amberlyst-15 as solid catalysts. This resulted in the minimization of harmful mineral acid wastes. The reactions of resorcinol with acrylic acid, propynoic acid, and ethyl acetoacetate were investigated in toluene and p-chlorotoluene under reflux conditions to obtain coumarins in 60%-80% yield (Hoefnagel et al. 1995 Gunnewegh et al. 1995). 

Amberlyst 15 has also been used in the von Pechmann coupling of ethyl acetoacetate to a variety of substituted phenols, such as resorcinol (8), to give substituted hydroxycoumarins such as 9 (eq 17). This reaction appears to occur efficiently with a substo-ichlometiic amount of Amberlyst 15 (25% w/w). 

The reactivity of the amino group can be strongly influenced by the presence of negative substituents in the amine molecule. For example, trinitroaniline and trichloroaniline do not react. On the other hand, in addition to primary aliphatic amines, aromatic amines, and amino acids, substances with an active methylene group also react (3). A positive reaction was also observed with substances such as guanidine, semicarbazide, phenyl-hydrazine, ethyleneimine, piperidine, piperazine, benzylcyanide, cyano-acetylacetone, diethyl malonate, ethyl acetoacetate, dibenzoylmethane, rhodanin, indole, methylphenylpyrazolone, resorcinol, phloroglucinol, and quaternary heterocyclic bases and oxonium salts. 

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