Coumarin 2- arylation

C-CN activation via oxidative addition can be followed by the activation of another C-C bond to develop cycloaddition reactions. The reaction of o-arylcarboxyben-zonitrile with alkynes proceeds in this manner to give coumarins, aryl cyanides, and an alkyne-arylcyanation product in the presence of catalytic amounts of nickel and aluminum-based Lewis acid (Scheme 18) [61]. Likewise, o-cyanophenyl-benzamides undergo the transformation to give quinolones (Scheme 18 [62]. A catalytic cycle involving a five-membered nickelacycle intermediate, generated possibly by the oxidative addition of Ar-CN bonds, and the subsequent C-C bond activation [63] is proposed (Scheme 19). 

Anthocyanidins were first synthesi2ed by reaction of an aryl Grignard reagent with a coumarin (93). 

Coumarin, 7-amino-7-(diethylamino)-, I, 333 Coumarin, 7-amino-4-methyl-fluorescence spectra, 3, 601 Coumarin, 7-amino-3-phenyl-brightening agents, I, 339 Coumarin, 4-aryl-occurrence, 3, 677 synthesis, 3, 810 Coumarin, 3-arylazo-4-hydroxy-structure, 3, 643 Coumarin, 3-bromo-reactions... 

The arylation of alkenes by treatment with a diazonium chloride (or bromide) solution and cupric chloride (or bromide) is called the Meerwein arylation reaction, after its discoverer (Meerwein et al., 1939). Originally, it was discovered using a,P-unsaturated carbonyl compounds, namely coumarin (Scheme 10-43) and cinnamic derivatives (Schemes 10-44 and 10-45). As Scheme 10-45 shows, the Meerwein reac-... 

Several aryl esters of 6-chloromethyl-2-oxo-2//-l -benzopyran-3-carboxylic acid act as human Lon protease inhibitors (alternate substrate inhibitors)46 without having any effect on the 20S proteasome. Proteasomes are the major agents of protein turnover and the breakdown of oxidized proteins in the cytosol and nucleus of eukaryotic cells,47 whereas Lon protease seems to play a major role in the elimination of oxidatively modified proteins in the mitochondrial matrix. The coumarin derivatives are potentially useful tools for investigating the various biological roles of Lon protease without interfering with the proteasome inhibition. 

Using Pd-mediated cross-coupling reactions, such as Suzuki, Heck, and Sonoga-shira- Hagihara reaction, researchers efficiently constructed a library of 151 coumarin derivatives from eight 3-bromocoumarins cross-coupled with ten aryl/heteroaryl boronic acids, ten alkenes, and ten alkynes (Fig. 4). 

Formation of mixtures of the above type, which is common with internal olefins, do not occur with many functionalized alkenes. Thus, tertiary cinnamates and cinnamides undergo cycloadditions with benzonitrile oxides to give the 5-Ph and 4-Ph regioisomers in a 25-30 75-70 ratio. This result is in contrast to that obtained when methyl cinnamate was used as the dipolarophile (177). 1,3-Dipolar cycloaddition of nitrile oxides to ethyl o -hydroxycinnamate proceeds regiose-lectively to afford the corresponding ethyl fra s-3-aryl-4,5-dihydro-5-(2-hydro-xyphenyl)-4-isoxazolecarboxylates 36 (178). Reaction of 4-[( )-(2-ethoxycarbo-nylvinyl)] coumarin with acetonitrile oxide gives 37 (R = Me) and 38 in 73% and 3% yields, respectively, while reaction of the same dipolarophile with 4-methoxy-benzonitrile oxide affords only 37 (R = 4-MeOCr>H4) (85%) (179). 

The arylation of alkenes was discovered by Meerwein146 in 1939 using ,/)-unsaturated carbonyl compounds, namely coumarin and cinnamic derivatives. Diazotizations for Meerwein reactions are made in aqueous HC1. The substitution proper may be combined with addition of HC1 to the double bond. As catalyst, CuCl2 is used. Various observations (see elsewhere7k) demonstrate that in typical Meerwein systems, part of Cu11 is reduced to Cu1. 

Correspondingly, the catalytic 1,4-addition of dialkylzinc reagents to 3-nitro-coumarin 89 (Scheme 7.24), with a fixed trans orientation of the aryl and nitro groups, proceeds with excellent yields (90-99%), high diastereoselectivity (d.r. up to 20 1), and enantioselectivities of up to 92%. Hydrolysis of the lactone moiety in 90 was accompanied by decarboxylation, providing an asymmetric synthesis of 8-aryl-nitroalkane 91. 

In the early 1970 s potent acaricidal activity in 3-aryl-4-hy-droxy-coumarins. III, and 2-aryl-l,3-indanediones, IV, and their enol esters was discovered at Union Carbide (1,2). Extensive synthesis and screening of analogs in the dione and enol ester series led to the field test candidates Va and Vb, active against both motile forms (mite) and eggs. Va and Vb embodied certain structural and physicochemical features shown by published QSAR studies (2,3) to be important in determining the level of activity in the 1,3-indanedione series (1) the dimension D2 across the aryl ring must be near 7A and symmetry is preferred (2) the... 

Rao, M.N., Krupadanam, G.L.D., and Srimannarayana, G., Four isoflavones and two 3-aryl-coumarins from stems of Derris scandens, Phytochemistry, 37, 267, 1994. 

Diketene is of course a masked form of acetoacetic ester, and as such reacts in much the expected manner with a variety of mono- and di-nucleophiles. Aromatic and heteroaromatic amines, and phenols, for example, give acetoacetanilides and aryl acetoacetates the latter can be cyclized in excellent yield to coumarins while reaction of the former with excess of diketene followed by cyclization gives dioxopyridines (e.g. equation 164). Amidines, ureas, thioureas, S- alkylthioureas and carbodiimides also react with diketene to give pyrimidines e.g. equation 165), although in the case of amidines, S- alkylthioureas and carbodiimides the initially formed products are 1,3-oxazines which are converted into pyrimidines on subsequent treatment with acid or base. 

Aryl acetoacetates, which may be obtained by the reaction of phenols with diketene, are cyclized on treatment with sulfuric acid (54JCS854). The yields of coumarins are similar to those obtained by a Pechmann reaction on the phenol. 

Benzocoumarins (405) result from the dehydrogenation of the corresponding dihydrocoumarins by palladium-charcoal at 300 °C in the absence of solvent (73CB62), whilst 4-aryl-3,4-dihydrocoumarins are converted to the coumarins in diphenyl ether (72IJC32). This latter conversion also occurs under milder conditions using iodine and potassium acetate in acetic acid (73AJC899). 

The use of preformed aryl acetoacetates seems to offer no advantage over the usual method, giving chromones or coumarins under the influence of the normal catalysts (54JCS854). 

Synthesis of the benzopyran ring has also been performed by microwave-assisted copper-catalysed cross coupling of an aryl iodide with terminal alkynes, in the presence of copper(I) iodide/triphenylphosphine (Scheme 3.35)56. An alternative approach involving microwave heating of mixtures of salicylaldehyde and various derivatives of ethyl acetate in the presence of piperidine has enabled rapid Knoevenagel synthesis of coumarin derivatives (Scheme 3.35)57. 

The establishment of equilibria (7), in some cases requires a considerable time. The wave corresponding to coumarin reduction after a time such that the wave shows no further decrease (11) can be utilized to calculate the equilibrium constants Kq and the effect of R1, R2 = alkyl or aryl can be shown (10). The linear dependence found between the half-wave potentials of coumarin and the 6-values indicates that the relative... 

Substituted 3-phenylcoumarins with methoxy [103] and triazinylamino groups [104] at the 7-position were developed later. These have been superseded in industry by the 3,7-bis[(hetero)aryl]coumarins [105-110],... 

Hydroxycoumarins can be converted into 4-arylcoumarins via the Pd-catalysed coupling of 4-stannylcoumarins with aryl iodides (95SC2883), whilst the three component reaction of 4-hydroxy-coumarins, triethyl orthoformate and hydrazines yields A-derivatives of 3-methylenechroman-2,4-diones (95M579). 

An asymmetric 1,4-addition of arylboronic acids to coumarins such as 220 catalyzed by rhodium has been achieved in greater than 99% ee (Equation 21) <2005OL2285>. This method should prove useful for the synthesis of enantiomerically enriched compounds that contain a stereogenic center between two aryl groups. This methodology was used in the total synthesis of (R)-tolterodine. 

The asymmetric catalytic hydrogenation of 4-aryl coumarins has been reported (Scheme 30) <1999TL3293>. Initial attempts to asymmetrically hydrogenate coumarin 240 directly proved unsuccessful. However, upon lactone opening, 241 was smoothly converted to hydrogenated product 242, which would relactonize to 243 gradually on standing or more quickly under catalysis with />-toluenesulfonic acid. 

A Pd-catalyzed Heck arylation with coumarin and bromobenzene has been reported (Equation 28) <1996IJB588>. Two products, 264 and 265, were reported for this reaction in a 3 1 ratio. The major compound was formed by a Heck reaction at the C-3 position, and mechanistic discussion was included for both products. 

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