Unusual nicotinoylation of 4-phenyl-5,7-dihydroxycoumarin

In the present work, we report a convenient synthesis of 5and 7substituted-4-phenyl coumarins. In contrast to previous results obtained with 4-alkylcoumarins, nicotinoylation of 5,7-dihydroxy-4phenylcoumarin with nicotinoyl benzotriazole or nicotinoyl azide selectively provides 5-O protected ester. The combination of the nicotinoylation reaction followed by tosylation-denicotinoylation yields 5-hydroxy-7-tosyloxy-coumarin derivative, which may be useful in the synthesis of inophyllum, a tetracyclic HIV reverse transcriptase inhibitor, as well as its analogues.


Introduction
Asymmetrically O-substituted 5,7-dihydroxycoumarins attract attention as important building blocks for the synthesis of biologically active compounds. Compounds of this class are widespread both in nature, especially in plants in the form of mono-and diterpenes, and in synthetic compounds with important biological activity [1][2][3][4]. They have anti-cancer, antibacterial [5,6], anti-HIV, antiinflammatory and others activities, For example, inophyllums (Fig. 1), a series of natural HIV reverse transcriptase inhibitors isolated from Calophyllum inophyllum tree [7], comprise asymmetrically O-substituted 5,7dihydroxycoumarin scaffold. Asymmetrically O-substituted 5,7-dihydroxycoumarins also can be used to prevent and treat Parkinson's disease, brain lesions, and dementia [8]. We have previously demonstrated that nicotinoylation of 5,7-dihydroxy-4-alkylcoumarins is a convenient method for the synthesis of both 5-and 7-hydroxy-substituted coumarins [9,10]. In this case, the nicotinoylation reaction proceeds at the sterically less hindered hydroxy group at position C7 of coumarin system (Scheme 1). Subsequent modification of free 5-OH hydroxy group with a protective group orthogonal to nicotinoyl (tosyl or di(tertbutyl)phenylsilyl) and removal of the nicotinoyl moiety under acidic conditions allows the synthesis of complementary 5-OH protected coumarins [9].
In the presented work, we expand this methodology of selective nicotinoylation to 4-aryl-5,7-dihydroxycoumarins.

Experimental
Unless otherwise noted, all commercially available compounds were used without further purification.

Results and discussion
We found that nicotinoylation of 5,7-dihydroxy-4phenylcoumarin 1 with nicotinoylbenzotriazole (X = benzotriazolyl) or nicotinic acid azide (X = N3) leads to unexpected 5-nicotinoyloxy-4-phenylcoumarin 2 (Scheme 2). Scheme 2 Nicotinoylation of 5,7-dihydroxy-4-phenylcoumarin The reaction takes place at most sterically hindered 5-OH position as confirmed by X-ray structural analysis of compound (Fig. 2). One may assume that the selectivity of this reaction is associated with non-covalent interactions in the transition state, such as π-π stacking between the pyridyl ring of nicotinoyl derivatives and the phenyl ring of coumarin. To obtain 5-hydroxy-7-O-subsituted derivatives of coumarin 1, we carried out the exchange of hydroxy protective groups. Thus, tosylation of 2 with p-toluenesulfonyl chloride followed by denicotinoylation of 3 in an acidic media provides 7-protected tosyloxy derivative 4 (Scheme 3). Compound 4 may be further converted to inophyllum or inophillum analogues using adapted procedures [9].

Conclusions
Thus, we presented a convenient synthesis of 5-and 7substituted 4-phenyl coumarins. It was demonstrated that 4phenyl-5,7-dihydroxycoumarins, unlike 4-alkyl compounds, react with nicotinoylazide with the involvement of the 5hydroxy group in the reaction. The structure of the nicotinoyl derivative was proved by X-ray diffraction analysis. Combination of the nicotinoylation with tosylationdenicotinoylation allows one to obtain 7-hydroxy protected 5,7-dihydroxycoumarins.