Synthesis of fluorescent dibenzopyranones by the Diels-Alder reaction of 4-styrylcoumarins and N -phenylmaleimide and in situ aromatization using DDQ

Reaction of 7-substituted-4-styrylcoumarins and N -phenylmaleimide in nitrobenzene under reflux conditions affords mainly 7-substituted-2,11-diphenyl-3a,10,11,11a-tetrahydro[1]- benzopyrano[3,4-e ]isoindole-1,3,4(2 H )-triones. The same reaction in o -dichlorobenzene in the presence of DDQ gives the corresponding aromatized dibenzopyranones. The dibenzopyranones are fluorescent and their UV and fluorescence spectra are reported.


Introduction
7] Such lactones have been used as intermediates in the synthesis of several pharmaceutically interesting compounds including progesterone, androgen, glucocorticoid modulators, [8][9][10] and endothelial cell proliferation inhibitors. 11Furthermore, dibenzopyranones occur naturally in many food sources including citrus fruits, herbs, and vegetables. 12There are several methods available for the synthesis of dibenzopyranones, the most common being Suzuki cross-coupling reaction followed by Lewis acid [13][14][15][16] or metal 17 mediated lactonization.More recently, the Diels-Alder cycloaddition of 4-cyanocoumarins (as dienophiles), 18 inverse electron demand Diels-Alder reaction of coumarin fused electron deficient dienes with electron rich dienophiles, [19][20][21] tert-butyllithium-mediated cyclization of bromobenzylfluorophenyl ethers, 22 and ruthenium-catalyzed cyclotrimerization of aryl diynes 23 have been reported.In 2002, Abbott Laboratories reported a practicable and scalable synthesis of glucocorticoid receptor A-224817.0through Negishi cross coupling. 24However, the disadvantages of these methods include low overall yield, long reaction time, low temperature conditions, multistep sequence, and the need to purify the intermediates.

Results and Discussion
7-Methyl-4-styrylcoumarin (1a) was prepared by a known method. 281a was subjected to Diels-Alder reaction with N-phenylmaleimide (2) (NPMA) in boiling nitrobenzene when adduct 3a was formed within 10 min.When the reaction was continued further, a small amount of the corresponding dehydrogenated aromatic product 4a was formed along with 3a.The reaction was continued up to 24 h to see whether compound 3a underwent retro Diels-Alder reaction.Instead, 3a underwent dehydrogenation slowly to form 4a indicating a nitrobenzene promoted dehydrogenation of 3a.This was confirmed by aniline produced in the reaction.0][31][32][33] Nitrobenzene is a known dehydrogenating agent, e.g. as in the Skraup synthesis. 34In the 1 H NMR, 4a showed a multiplet at 7.29-7.55δ corresponding to aromatic 12 H, a doublet at 8.02 δ for C1H, and a singlet at 8.35 δ for C10H, indicating the dehydrogenation of 3a to 4a.No signal was observed for aliphatic protons.The dehydrogenation step, i.e. 3 to 4, was studied further in order to confirm the role of nitrobenzene.3a was heated separately in boiling nitrobenzene.The dehydrogenation reaction was very slow and only 9% of 4a was formed in 24 h.The Diels-Alder adducts 3b (R=OH), 3c (R=OMe) and 3d (R=H) also gave the corresponding dehydrogenated products 4b, 4c and 4d respectively, in low yield on heating in boiling nitrobenzene (Table 1).In order to see the effect of NPMA on the dehydrogenation, we carried out the Diels-Alder reaction with an increasing amount of NPMA.However, the quantity of NPMA was not found to have any effect on the dehydrogenation (Table 2).Reaction conditions: 1a (0.262 g, 1 mmol); nitrobenzene: 5 mL; Temp: Reflux; b Time for which reaction was continued; c Isolated yield.
The dehydrogenation of 3a was attempted in the presence of Pd/C (10%), sulfur, napthoquinone, and DDQ, in different solvents (Table 3).DDQ in nitrobenzene and odichlorobenzene (o-DCB) was found to be the most effective dehydrogenating agent.In xylene, 3a was partly soluble at the reflux temperature and only a trace of the product was obtained.
Our next objective was to develop a one-pot process, where the Diels-Alder reaction and dehydrogenation would occur subsequently.1a was reacted with NPMA in boiling nitrobenzene or o-dichlorobenzene, in the presence of DDQ by varying the mole ratio for NPMA and DDQ (Table 4).Two equivalents of DDQ and three equivalents of NPMA in o-DCB gave 73% yield of 4a in 1 h.In nitrobenzene, the required time for Diels-Alder-dehydrogenation reaction was shorter, but the yield obtained was 48% and 49% using two and three equivalents of DDQ, respectively.Surprisingly, though the Diels-Alder reaction in o-DCB was slower as compared to nitrobenzene, the yield in o-DCB was better.Reaction conditions: 1a (0.262 g, 1 mmol); Solvent (5 mL); a Reflux temperature; b Time for which reaction was continued; For entries (1-6) -NPMA used 3 equiv.;For entries (7-9) -DDQ used 2 equiv.; c Isolated yield.
Using the optimized conditions we carried out the reactions for other substrates to study the generality of tandem Diels-Alder-Dehydrogenation reactions.Different 4-styrylcoumarins were prepared by the known procedure. 28They were reacted with NPMA under the optimized conditions to obtain a series of dibenzopyranones (4) (Table 5).Reaction conditions: mole ratio (1: NPMA) 1:3 equiv.; 1: DDQ 2 equiv.; a Reflux temperature; b Time for which reaction was continued; c Isolated yield.
Compounds 4 showed fluorescence.Hence, their UV absorption and emission properties were studied in chloroform + methanol (1:1, v/v) (Figure 1, Table 6).In the same solvent system standards anthracene and fluorescein show fluorescence at 488 and 513 nm respectively.UV (λabs max) and emission (λf max) depended upon the nature of the substituent on the coumarin ring.High stoke shift (Δλf-abs) was observed in the case of 4a, 4b, and 4c.This may be ascribed to the increased π-electron density on the coumarin ring, due to the presence of electron donating groups -Me, -OH, -OCH3.The other substituents showed poor stokes shift.

Conclusions
We have developed a protocol for the synthesis of dibenzopyranones by the tandem Diels-Alder dehydrogenation reaction.DDQ in o-dichlorobenzene is the best dehydrogenating agent.These dibenzopyranones are pale yellow to yellow in color and show emission under UV light (365 nm).

Experimental Section
General.The melting points were determined on an Analab melting point apparatus (Model-µThermocal 10) in open capillary tubes and are uncorrected.The IR spectra were recorded on a Perkin-Elmer spectrum-100 FTIR spectrophotometer.The 1 H NMR spectra were recorded on Varian Mercury plus 300 (300 MHz) spectrometer in CDCl3/DMSO-d6 with TMS as an internal standard and the chemical shifts are expressed in  unit (ppm).The Mass spectra were recorded on a Finnigan LCQ Advantage Max spectrometer.Elemental analysis was carried out on a Thermo finnigan, Flash EA 1112.UV spectra were recorded on a Shimadzu UV-1601, UV-VIS Spectrophotometer.Fluorescence spectra were recorded on a Cary Eclipse fluorescence Spectrophotometer.Absorption and Emission spectra were performed using quartz cell (1 x 1 cm).All compounds are excited at their absorption values shown in table no 6.Emission range Diels-Alder reaction followed by dehydrogenation reaction of 1a with NPMA (2) without DDQ in nitrobenzene.1a (0.262 g, 1 mmol) and NPMA (0.519 g, 3 mmol) were refluxed in nitrobenzene (5 mL) for 24 h.The solution was cooled to room temperature, n-hexane (15 mL) was added and the solution stirred for 30 min.The precipitated solid was filtered and subjected to column chromatography to obtain 4a using silica gel in chloroform.
General procedure for dehydrogenation of Diels-Alder adduct (3) in nitrobenzene 3 (1 mmol) was refluxed in nitrobenzene (5 mL) for 24 h.The solution was cooled to room temperature.n-Hexane (15 mL) was added and the solution was stirred for 30 min.The precipitated solid was filtered and subjected to column chromatography using silica gel in chloroform.
Tandem Diels-Alder dehydrogenation reaction of 1a in nitrobenzene.1a (0.262 g, 1 mmol), NPMA (0.519 g, 3 mmol) and DDQ (0.454 g, 2 mmol) were refluxed in nitrobenzene for 15 min.After the completion of reaction, the solution was cooled to room temperature.n-Hexane (15 mL) was added to the solution and stirred for 30 min.The solvent was decanted and the insoluble mass was subjected to column chromatography using silica gel in chloroform.
General procedure for tandem Diels-Alder dehydrogenation reaction in o-dichlorobenzene 1 (1 mmol), NPMA (0.519 g, 3 mmol) and DDQ (0.454 g, 2 mmol) were refluxed in odichlorobenzene for 1 h.After the completion of reaction, the solution was cooled to room temperature.Reduced DDQ was separated from the reaction mixture by filtration.n-Hexane (15 mL) was added to the filtrate and stirred for 30 min.The solvent was decanted and the insoluble mass was subjected to column chromatography using silica gel in chloroform.

Table 2 .
Effect of increasing quantity of NPMA in the reaction with 1a on the yield of 4a

Table 3 .
Conversion of 3a to 4a using of different dehydrogenating reagents and solvents Reaction conditions: 3a (0.435 g, 1 mmol); Solvent (5 mL); a Reflux temp; b Time for which reaction was continued; c Isolated yield.

Table 4 .
Diels -Alder reaction of 1a and NPMA using different mole ratios of NPMA and DDQ in nitrobenzene and o-dichlorobenzene (o-DCB)

Table 5 .
Tandem Diels-Alder-dehydrogenation reaction of 1 with NPMA in o-dichlorobenzene a