Synthesis of 3-Substituted Coumarins

This important class of compounds has been prepared by flash vacuum pyrolysis in an attempt to circumvent the variable yields and inconvenient work-ups encountered in Wittig olefination-cyclizations, and more recently, a rhodium-catalyzed process was introduced that produces a mixture of coumarins and benzofurans in variable yields [133]. 

While our product yields (80 to 95 %) are not generally superior to those reported in the literature, they are competitive. Moreover, the mild conditions and the shorter reaction times in our methodology constitute a more practical alternate route to coumarins. 

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Fig. 5.8 Alkenes 19, (hetero)aryl boronates 20 and terminal alkynes 21 applied in the combinatorial synthesis of 3-substituted coumarins.

Coumarins. - There is interest in the synthesis of 3-substituted coumarins cyclization of substituted salicylaldehydes with cyanoacetamide, followed by treatment with phosphoryl chloride in DMF, has given coumarin-3-carbonitriles. High yields of 3-phenylcoumarins were obtained when ortho-hydroxy-aldehydes or -ketones were treated with phenylacetyl chloride-potassium carbonate.When cyclohexane-1,3-diones (187) were condensed with triethyl orthoformate and either urea and thiourea and the initial product (188) was allowed to condense with nitriles, the 3-carboxamide (189) was obtained in good yield.The antibacterial activity of some sulphones has prompted the synthesis of 3-arylsulphonyl-coumarins by oxidation of sulphides. ... 

A dual catalyst system piperidine-iodine was used in the synthesis of 3-substituted coumarins through a one-pot three-component reaction of salicylaldehyde derivatives, P-keto esters, and l-(2-aminophenyl)pyrrole in DMF at room temperature (14T2048) and through a four-component reaction of salicylaldehyde derivatives, P-keto esters, ammonium acetate, and isatoic anhydride in DMF at 60°C (Scheme 55) (14SL1596). 

Table 7.2 Synthesis of 3-substituted coumarins in aqueous and ethanolic media...

Conjugate addition products 322 and 323 have been subjected to hydro-genolysis in the presence of 10% Pd/C catalyst (Scheme 4.103). " 3-Substituted coumarins 324 were obtained in 50-66% yields from substrates 322 through fission of the benzyl ether and spontaneous cyclization via acyl substitution. Using compounds 323 as substrates, piperidinyl derivatives 325 were obtained in 45-61% yields, and the de-aminated derivatives 326 were also acquired in 9-21% yields. Such a synthetic method may enable the synthesis of multi-substituted coumarins (2//-l-benzopyran-2-ones), which are widely distributed in nature and many of which exhibit pharmacological activities. 

Although various methods were reported for the synthesis of 4-substituted coumarin, inconvenient reaction conditions were utilized in most of the previously reported reactions [109]. As mentioned before, route A in Scheme 3.7 is the most widely used in the synthesis of the title compound. For example, Yang described the preparation of 4-substituted coumarin using palladium-catalyzed cross-coupling reaction of 4-tosylcoumarins [110a] and nickel-catalyzed... 

Even though the route A could provide a variety of 4-substituted coumarins, a drawback to this procedure is that some of the organometallic reagents are not readily available. Therefore, in spite of the present methodologies, there is still a need to explore a versatile synthetic methodology for the construction of a chemical library of 4-substituted coumarin derivatives. We considered the alternative route to the synthesis of 4-substituted coumarins, depicted by route B in Scheme 3.7. We assumed that this route could provide a versatile vray of introducing a variety of different substituents at the 4-position of coumarin. The direct preparation and application of 4-coumarinylzinc bromide represents a novel and versatile approach to many new substituted coumarins [113]. 

It is noteworthy to mention the efficient procedure for the synthesis of 4-substituted coumarins through the Pechmann reaction (a trans-esterification/ acylation reaction) using BiCl3 or Bi(N03)3 5H20 as catalysts (Equation 33) [66]. 

The Michael addition of nucleophiles to coumarins catalyzed by solid bases provides an interesting approach to the synthesis of 4-substituted 3,4-dihydrocumarins, because with the conventional Michael catalysts the alkaline hydrolysis of the 8-lactone predominates (Scheme 44). Results were obtained when the Michael addition of diethyl malonate to coumarin was catalyzed by the activated Ba(OH)2 292). An unusual 1,2-addition-elimination process at the C = 0 bond was observed. The mechanism of this reaction was explained on the basis of the microcrystalline structure of the catalyst. It was suggested that the rigid coumarin molecule interacts with the Ba ions through the lone-pair electrons of both oxygen atoms of the... 

Substituted coumarins arise from the use of 2-substituted 1,3-dicarbonyl compounds. The synthesis of a number of such keto esters has been described together with their conversion into the coumarin (65JOC4114). The use of hydrogen fluoride in place of sulfuric acid as condensing agent was found to be very advantageous. 

Rezayan, P. Azerang, S. Sardari, A. Sarvary, Chem. Biol. Drug Des. 2012, 80,929-936. Synthesis and biological evaluation of coumarin derivatives as inhibitors of mycobacterium bovis (BCG), (c) A. Shaabani, A. Sarvary, E. Soleimani, A. H. Rezayan, M. Heidary, Mo/. Divers. 2008,12,197-202. A novel method for the synthesis of snbstitnted 3,4-dihydro-coumarin derivatives via isocyanide-based three-component reaction, (d) A. Shaabani, E. Soleimani, A. H. Rezayan, A. Sarvary, H. R. Khavasi, Org. Lett. 2008, 10, 2581-2584. Novel isocyanide-based four-component reaction a facile synthesis of fuUy substituted 3,4-dihydrocoumarin derivatives. 

The Pechmaim reaction has found extensive appHcations for the synthesis of numerous coumarin derivatives (39). Coumarin derivatives substituted in the pyrone ring can be obtained by condensing phenol with beta-ketoesters. For example, 4-methylcoumarin (3) is obtained with ethyl acetoacetate... 

Synthesis of the coumarin derivative 11.58 containing two isomeric triazolyl rings is indicated in Scheme 11.24- The substituted pyrazolyl derivative of naphthalimide 11.59 is prepared by a reaction sequence somewhat similar in principle to that already shown in Scheme 11.14, using 4-amino-1,3,5-trimethylpyrazole in the penultimate step followed by quaternisation. 

Watson BT, Christiansen GE (1998) Solid phase synthesis of substituted coumarin-3-carbox-ylic acids via the knoevenagel condensation. Tetrahedron Lett 39 6087-6090... 

Another example of fluorescence intensity modulation in cou-marins is the 3-azido substitution that quenches the fluorescence completely. These compounds are used as starting material for the synthesis of fluorescent triazolocoumarins by click chemistry [31], Interestingly, the fluorescence of some coumarins depends strongly on the solvent. This is the case for 7-alkoxycoumarins that have been used as probes for microenvironments [32], 7-hydroxycoumarin that is pH sensitive, and 7-NR2 substituted coumarins such as coumarin 120 whose quantum yield is reduced in nonpolar solvents due to a change in the 3D structure [33],... 

In addition to the examples of coumarin syntheses given in the reviews mentioned above and in the treatise on heterocyclic compounds (B-51MI22400), more recent studies have made use of the Perkin synthesis. These include the use of substituted phenoxyacetic acids to prepare 3-phenoxycoumarins (78CI(L)628> and the synthesis of chlorocoumarins from chlorosalicylaldehydes (81T2613). The use of DBU in place of sodium acetate was necessary to effect the ring closure of a number of o-hydroxyketones (78BCJ1907). 

De la Hoz et al. have studied the microwave-assisted synthesis of substituted coumarins by the condensation of phenol, 1,3-dihydroxybenzene/l,3,5-trihydroxy-benzene and propynoic/propenoic acids55. The examples illustrate that the application of heterogeneous supported catalysts can eliminate the production of acidic waste streams, associated with conventional Lewis acid catalysts. This synthetic approach constitutes an interesting alternative to the Pechman reaction (Scheme 3.34). 

Kulkarni MV, Patil VD, Biradar VN,Nanjappa S (1981) Synthesis and biological properties of some 3-heterocyclic substituted coumarins. Arch Pharm (Weinheim) 34(5) 435... 

Kusanur R, Ghate M, Kulkarni MV (2004) Synthesis and biological activities of some substituted 4- 4-(l,5-diphenyl-lH-pyrazol-3-yl)phenoxymethyl coumarins. Indian J Het Chem 13 201... 

Li et al. [30] gave the solvent free synthesis of 2-aryl-5-(coumarin-3 -yl)-l,3,4-oxadiazoles (xxv) in high yields by reacting the coumarin-3-carboxylic acid (xxiii) with (un)substituted benzoic acid hydrazides (xxiv) in presence of PEG supported dichlorophosphate under microwave irradiation. 

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... 

The Perkin reaction involves the condensation of a carboxylic acid anhydride and an aldehyde in the presence of a weak base, often the sodium or potassium salt of the acid or triethylamine, to give unsaturated carboxylic acids (equation 1). The first example of this reaction was described by Perkin in 1868 and involves a synthesis of coumarin by heating the sodium salt of salicylaldehyde with acetic anhydride (equation 2). The reaction is generally applicable only to aromatic aldehydes and is particularly useful for the preparation of substituted cinnamic acids, as illustrated by equation (3). ... 

The Pd-catalysed reaction of phenols with propynoic acids offers an atom-economic and green route to coumarins. Although the reaction with propynoic acid itself is not regioselective, 3-phenylpropynoic acid gives a single product from w-substituted phenols <04S1466>. The synthesis of coumarins both from alkynes, CO and iodophenols and by the reaction of phenols with propiolic esters is facilitated by Co/Rh nanoparticles <04SL2541>. 

In the synthesis of coumarins by the von Pechmann reaction, a spiro-compound (251) was simultaneously formed from 4-chloro-2-methylphenol (and from 2,3,5-trimethylphenol). A possible mechanism for this reaction involves the formation of the lactone (252), which reacts with another molecule of the phenol. The condensation of the dicyano-ester (253) [obtained from malononitrile and ethyl cyanoacetate] with substituted o-hydroxybenzaldehydes yields substituted coumarinimines, e.g. (254).A series of 4,6,7-substituted coumarins have been prepared and assessed for their suitability in fluorescence labelling of polymers. Esters of the type PhCH CRCOaAr react with AICI3 to give coumarins, which are probably formed via dihydrocoumarins (255) by dearylation. ... 

The condensation of salicylaldehyde or its derivatives with various derivatives of ethyl acetate in the presence of piperidine led to the synthesis of coumarins 95 in 55-94% yields under solvent-free conditions using MWI. Similarly, the benzo analogs 96 were prepared in 75-82% yields from 2-hydroxy-1-naphthaldehyde within 3-lOmin (Scheme 19) (98JCR(S)468). However, naphtho[2,l-Z ]pyran-3-ones 96 were prepared in 58-67% yields from the same aldehyde and substituted acetic acids under MWI for 6-8 min but in the presence of DCC and using DMSO as a solvent (Scheme 19) (97JCR(S)178). 

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