Dihydrofurocoumarinones - new useful intermediates for substituted and condensed furocoumarins

Survey of new synthetic paths to substituted and condensed furocoumarins, perspective compounds for photochemotherapy is given. These furocoumarin syntheses are based on the use of dihydrofurocoumarinones as convenient synthons. Both dihydrofuro[2,3-h]coumarin-9-ones and dihydrofuro[2,3-g]coumarin-6-ones became available via the unusual Fries rearrangement of 7-hydroxycoumarin chloroacetates. Substitution and keto-enol reactions of dihydrofurocoumarinones followed by aromatization of dihydrofuranone moiety are key steps of substituted and condensed furo[2,3-h]- and furo[2,3-g]coumarins synthesis. We have already characterized in our previous papers many of the compounds listed in the survey. The structures of new compounds are proved by mass spectral, 1H NMR spectral and elemental analysis data


Introduction
Furocoumarin derivatives, natural photosensitive compounds have been found to be useful for medical treatment of skin diseases [1,2].Furocoumarin/ultraviolet therapy, known as photopheresis, has recently been used for treatment of cutaneous T cell lymphoma, Sezary syndrome and related diseases [3,4].Photochemotherapeutic effect of furocoumarins is based on intercalation of the furocoumarin molecule between pyrimidine bases of the microorganism DNA.The intercalation is then followed by the UV light activated cycloaddition reactions of furocoumarin with pyrimidine bases.These [2+2] photocycloaddition reactions provide thus a cross-link of DNA and prevent a microorganism reproduction.

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Page 525  ARKAT USA, Inc 6-Chloroacetyl-7-hydroxy-4-methyl-8-R-coumarins 6a,b have also been found in the reaction mixtures.They seem to be the key intermediates in the unusual way of Fries rearrangement of 7hydroxycoumarin chloroacetates.wavelength absorption bands in the UV spectra have been found at 330 nm in methanol and at 285 nm in CCl4.We have assigned the band at 330 nm to the enol form absorption, since its PPP CI-calculated position is located at 328 nm.Both semiempirical and nonempirical quantum chemical calculations showed the keto form to be a predominant one.The difference between formation energies of keto and enol forms has been found equal to -10.57 and -8.82 kcal/mol by AM1 and PM3 calculations respectively.Keto-enol tautomeric transformation of 4-methyldihydrofuro[2,3-h]coumarin-9-one 2b turned to be a key way of many its reactions.We have carried out chlorination and bromination of the compound 2b with a good yield [24].For example, treatment of 2b by bromine in acetic acid or 1,4-dioxane provides its mono-and dibromination.

Scheme 6
We have studied azo-quinone hydrazone tautomeric transformations of the compounds 13 with use of electron absorption spectra and quantum chemical calculations, both semiempirical and nonempirical.Hydrazone tautomeric forms have been found to be the predominant ones.For example, a good correlation between calculated by the PPP CI method and experimental positions (λ max) of the longest-wavelength absorption bands has been found when anti-isomer of quinone hydrazone form used as a model in the calculations [25] (Table 1).Calculated by the PPP CI method and experimental positions (λ max) of the longest-wavelength absorption bands of the compounds 13 a-d.N-H Singlet signal at 11.0-11.3ppm in the 1H NMR spectra and characteristic peaks in the mass spectra approve quinone hydrazone tautomeric form of the azocompounds 13.NH-Function in the compounds 13 has been acetylated [25] with formation of N-acetyl quinone hydrazones 14.
Scheme 9 There are some comments to the acetylation procedure.When acetylation is carried out by acetic anhydride in the presence of potassium acetate, 9-acetoxy-derivatives 20 are the final products.When compound 2b is treated by acetic anhydride in presence of sulfuric acid or pyridine, both O-acetylation and C-acetylation take place with formation of diacetyl-derivative 20h.
Acetylation of 7g provides rather an unusual result.Dimer 21 has been isolated as a main product.The following steps of aldehyde 7g transformation can be suggested: 7g undergoes partly decarbonylation along the acetylation procedure.The formed amount of 2b reacts then with the starting aldehyde 7g via croton condensation with formation of 21 (Scheme 10).

Scheme 10
Linear dihydrofuro[2,3-g]coumarin-6-ones 3 and 5 seem to undergo keto-enol transformations as well.Nevertheless an isosbestic points have not been seen in their electron absorption spectra when CCl4-MeOH mixtures are used as solvents.We have found the differences between formation energies of keto and enol tautomeric forms of 3b to be much higher, when compared with that of the 2b tautomeric forms: -15.72 and -12.57kcal/mol by AM1 and PM3 calculations respectively.Keto form of 3b turns to be relatively more stable one.Nevertheless dihydrofuro[2,3-g]coumarin-6-ones seem to be similar in reactivity to dihydrofuro [

Scheme 12
Position 8 seems to be rather reactive in the amine 16a.If condensations of amine 16a with benzaldehyde, pentafluorobenzaldehyde and 3,4,5-tris(methoxy)benzaldehyde take place in acetic acid in the presence of concentrated hydrochloric acid, reactions go at the position 8 only (leaving 6-amino function untouched) with formation of C-benzylidene derivatives 28a-c respectively.
These derivatives are analogues of C-benzylidene derivatives, which we have earlier studied in more detail [24].C-H-Bond seems to be more nucleophilic in these conditions than the 6amino function.
Moreover, pentafluorobenzaldehyde, the most active benzaldehyde reacts only at the position 8 of 16a in the presence of HCI.One can suggest, N-protonation decreases concentration of the active form of amin 16a.Benzylidene derivative 28a undergoes easily an acetylation and formylation in standard procedures with formation of compounds 29a, b respectively (Scheme 13).