4-Hydroxycoumarins 3-alkylated

Reaction of 2-chloromethyl-4//-pyrido[l,2-u]pyrimidine-4-one 162 with various nitronate anions (4 equiv) under phase-transfer conditions with BU4NOH in H2O and CH2CI2 under photo-stimulation gave 2-ethylenic derivatives 164 (01H(55)535). These alkenes 164 were formed by single electron transfer C-alkylation and base-promoted HNO2 elimination from 163. When the ethylenic derivative 164 (R = R ) was unsymmetrical, only the E isomer was isolated. Compound 162 was treated with S-nucleophiles (sodium salt of benzyl mercaptan and benzenesulfinic acid) and the lithium salt of 4-hydroxycoumarin to give compounds 165-167, respectively. 

Hydroxycoumarins are alkylated under extremely mild basic liquiddiquid phase-transfer catalytic conditions to produce the ethers and 4-alkylated derivatives 141 ]. The major product tends to be the ether (50-60%) but the yield of the C-alkyl-ated product is significant with allyl bromide and with propargyl bromide, where rearrangement of the allenic derivative occurs. 

A variety of other carbon nucleophiles have been alkylated with alcohols including malonate esters, nitroaUcanes, ketonitriles [119, 120], barbituric acid [121], cyanoesters [122], arylacetonitriles [123], 4-hydroxycoumarins [124], oxi-ndoles [125], methylpyrimidines [126], indoles [127], and esters [128]. Selected examples are given in Scheme 35. Thus, benzyl alcohol 15 could be alkylated with nitroethane 147, 1,3-dimethylbarbituric acid 148, phenylacetonitrile 149, methyl-pyrimidine 150, and even f-butyl acetate 151 to give the corresponding alkylated products 152-156. 

Scheme 16 3-Alkylated 4-hydroxycoumarins the core structure for various warfarin derivatives...

The nucleophilic core of 4-hydroxycoumarin (Scheme 18) represents the enolic form of 1,3-dicarbonyl functionality, which was efficiently alkylated with a low amount of Bi(OTf)3 (Schemes 11 and 12). Therefore, Rueping et al. investigated a Bi(OTf)3-catalyzed benzylation of 4-hydroxycoumarins [52],... 

Several important natural compounds have an alkyl chain at the C-3 position of 4-hydroxycoumarins. In a synthesis of 3-geranyl-coumarin, 4-hydroxycoumarin was reacted with an aldehyde to generate intermediate 194, which was trapped with thiophenol to produce 195. Reduction of 195 under hydrogenation conditions in the presence of Raney-Ni catalyst afforded alkylated 4-hydroxycoumarin 196 <19970PP223> (Equation 18). 

In conclusion, we have synthesized 4 (R = alkyl/aryl) in excellent yield compared to earlier reports by modifying the solvent for the rearrangement of 33. A synthetic route to previously unreported 3-(alkylaminomethylene)chroman-2,4-diones 31 (R = alkyl) with moderate yields has been revealed and those compounds have been shown to be the synthetic equivalents of the versatile substrate 3-formyl-4-hydroxycoumarin. 

Alkyl 6-Bromo-7-hydroxycoumarin-4-ylmethyl Carbonate (Bhcmoc)... 

By reaction of phenols with bifunclional molecules, which are able to alkylate and to esterify, several coumarin derivatives have been prepared using H-Bela as the catalyst. Thus resorcinol and propynoic acid react at 150 °C in p-chlorotolucnc as the solvent towards the perfumery ingredient umbelliferone (7-hydroxycoumarin) in good yield, 60 %, [84], Amberlyst-15 gave 40 % yield. II-Beta catalyzes the esterification as well as the ring closure alkylation step. 

Rhodium(II)-catalyzed reactions between diazosulfones and aldehydes yielded an entry to carbonyl ylides, which underwent inter- and intra-molecular cyclization reactions with dipolarophiles, such as alkynes and alkenes, to afford tetrasubstituted furans in modest to good yields <01SL646>. The rhodium(ll) acetate catalyzed reaction of 3-diazobenzopyran-2,4(3 -dione with terminal alkynes provided a mixture of 2-substituted furo[3,2-c]coumarin and furo[2,3-f ]coumarin, presumably through a formal [3+2] cycloaddition reaction <01S735>. Furo[3,2-c]coumarins were also produced from 4-hydroxycoumarins and a-haloketones via a tandem 0-alkylation-cyclization procedure <01TL3503>... 

A recent pubHcation has described the efficient ruthenium-catalyzed C-3 reductive alkylation of 4-hydroxycoumarin by dehydrogenative oxidation of benzylic alcohols. The optimization of reaction parameters, such as type of catalyst, type of solvent, activation method, reaction time, temperature, and base, was performed (Scheme 48). Under optimized conditions, using [RuCl2(PPh3)3] as catalyst in /erf-amyl alcohol under MW irradiation at 140 °C for 2 h, afforded a satisfying selectivity/conversion. 

Scheme 48 MW-assisted selective C-3 alkylation of 4-hydroxycoumarin with benzyl alcohol. ...

Montagut-Romans A, Boulven M, Lemaire M, Popowycz F. Efficient C-3 reductive alkylation of 4-hydroxycoumarin by dehydrogenative oxidation of benzybc alcohols through ruthenium catalysis. New J Chem. 2014 38 1794-1801. 

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