3-Acyl-4-hydroxycoumarins

Further work in this area showed that only one of the cou-marin rings was needed for biologic activity. Condensation of the hydroxyacetophenone, 4, with diethyl carbonate affords 4-hydroxycoumarin (2). The reaction may involve the 3-ketoester (5) cyclization of this would afford 2. Alternately, the reagent may first give the 0-acyl derivative cyclization as above will give the same product. Michael condensation of the coumarin with benzalacetone (6) affords the anticoagulant warfarin (named after its place of origin Wisconsin Alumni Research Foundation,... 

Phenprocoumon Phenprocoumon, 3-(a-ethylbenzyl)-4-hydroxycoumarin (24.1.14), is synthesized by acylating sodium salts of diethyl ester (l-phenylpropyl)butyric acid with acetylsalicylic acid chloride, which forms the compound 24.1.12, which upon reaction with sodium ethoxide cyclizes to 3-(a-ethylbenzyl)-2-carboethoxy-4-hydroxycoumarin (24.1.13). Alkaline hydrolysis of this product and further decarboxylation gives phenprocoumon (24.1.14) [21-28]. 

The fragmentation patterns of 4-hydroxycoumarins which possess a carbonyl function (as an ester or an acyl group) at C-3 have been studied in considerable detail (66JCS(C)1712). 

Coumarins, too, fluoresce, notably when an electron-releasing group is present at the 7-position. For example, A-acyl derivatives of some 7-aminocoumarins serve as fluorescent markers for the detection of proteinases (80MI22403). Coumarins show a propensity to absorb UV light and this results in a number of applications. A particularly simple illustration is the use of umbelliferone, 7-hydroxycoumarin, in sun-screen lotions. 

In an extension to the above methodology, a sequential 1,2-addition, dehydration, and in situ ring closure via a 67t-electron electrocyclic cyclization has been described in the context of the pharmacologically relevant natural products warfarin A, the arisugacins, merulidial, and isovelleral (Scheme 20) <2005CAR1287>. Carbohydrate-derived a,3-unsaturated enals were coupled with 4-hydroxycoumarin 188 and 4-hydroxy-6-methylpyran-2//-one 191 in the presence of proline catalysts to provide pyrone-annulated products of types 190 and 192. Stereoselective electrocyclic ring closure was observed only when hydroxyl functionality (at any of R -k ) on the enal was acyl protected. 

In the presence of a ruthenium catalyst, 3-diazochroman-2,4-dione 716 undergoes insertion into the O-H bond of alcohols to yield 3-alkyloxy-4-hydroxycoumarins 717 (Equation 285) <2002TL3637>. In the presence of a rhodium catalyst, 3-diazochroman-2,4-dione 716 can undergo insertion into the C-H bond of arenes to yield 3-aryl-4-hydroxy-coumarins (Equation 286) <2005SL927>. In the presence of [Rh(OAc)2]2, 3-diazochroman-2,4-dione 716 can react with acyl or benzyl halides to afford to 3-halo-4-substituted coumarins (Equation 287) <2003T9333> and also with terminal alkynes to give a mixture of 477-furo[3,2-f]chromen-4-ones and 4/7-furo[2,3-3]chromen-4-ones (Equation 288) <2001S735>. 

Solventless reactions of 5(4//)-oxazolones 139 with hydroxycoumarins 140 exhibited excellent control of chemoselectivity leading to O- and C-acylation products 141 and 142 <03SL1710>. 

V. Snieckus and co-workers developed a new carbamoyl Baker-Venkataraman rearrangement, which allowed a general synthesis of substituted 4-hydroxycoumarins in moderate to good overall yields. The intermediate arylketones were efficiently prepared from arylcarbamates via directed ortho metallation and Negishi cross coupling. The overall sequence provided a regiospecific anionic Friedel-Crafts complement for the construction of ortho-acyl phenols and coumarins. 

Hydroxylated aromatic ketones represent valuable intermediate compounds in the synthesis of important fragrances and pharmaceuticals. For example, the resorcinol acylation products are employed for the production of valuable fine chemicals such as 4-0-octyl-2-hydroxybenzophenone (UV light absorbent for polymers) and ipriflavone (antiosteopenic drug). a-Hydroxyacetophenone (o-HAP) and p-hydroxyacetophenone (p-HAP) are widely used for the synthesis of aspirin and paracetamol (4-acetaminophenol), respectively [103]. a-HAP represents also a key intermediate for the production of 4-hydroxycoumarin and warfarin, which are both used as anticoagulant drugs in the therapy of thrombotic disease [104], and it is also employed for the synthesis of flavo-nones [105,106]. 

Baker, W. Collis, C. B. Fluorescent acylating agents derived from 7-hydroxycoumarin. J. Chem. Soc. (Suppl.) 1949, SU-S15. 

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