Synthesis of Functionalized Dihydrofurocoumarin Derivatives from 3-Aminoalkyl-4-hydroxycoumarin

Abstract Some dihydrofuro-fused coumarin derivatives were synthesized from 3-aminoalkyl-4-hydroxycoumarin via in situ generation of N-ylide. The 3-aminoalkylated 4-hydroxycoumarin derivatives were synthesized from one-pot, three-component reaction of 4-hydroxycoumarin, aryl aldehydes, and secondary amines in ethanol at room temperature. Again, when salicylaldehyde was employed instead of benzaldehyde, interestingly pyranocoumarins were obtained. The reaction protocol can be further explored toward the synthesis of many other heterocyclic fused dihydrofurans. GRAPHICAL ABSTRACT


INTRODUCTION
Fused coumarin system, in particular furocoumarins, are secondary metabolites found in some higher plants such as celery (Apium graveolens), parsnip (Pastinaca sativa), and carrot (Daucus carota). [1] Naturally occurring furocoumarins exist either in the linear form where the furan is attached at the C(6) and C(7) or in the angular form, carrying the substituent at C(7) and C(8). The most abundant linear furocoumarins are psoralen, xanthotoxin, and bergapten, whereas the angular form is mostly represented by angelicin, sphondin, and pimpinellin ( Fig. 1).
Furocoumarin derivatives possess diverse biological activities such as antifungicidal, [2] insecticidal, [3] insect antifeedant, [4] anti-HIV, [5] and anticancer activities. [6] They have also attracted considerable attention because of their photochemical, photophysical, and photobiological activities. [7] Furocoumarins are photosensitizers of plant origin and increase the sensitivity of biological objects to UVA radiation. Because of these properties, furocoumarins have a wide range of applications as drugs for skin and autoimmune disease and thus are useful for molecular manipulation. [8] Some of the biologically important furocoumarins are shown in Fig. 2.
As a part of our continuing efforts toward the synthesis of various heterocyclic compounds, [9] particularly annelated coumarins of biological importance, [10] we report here the synthesis of some functionalized dihydrofurocoumarin derivatives 7 from the reaction of 3-aminoalkyl-4-hydroxycoumarin 6 and pyridinium salt 3 in the presence of a catalytic amount of 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) in acetonitrile under refluxing condition (Scheme 2).

DISCUSSION
We initiated our study with the three-component reaction of 4-hydroxycoumarin 1a, benzaldehyde 2a, and pyridinium salt 3a under refluxing conditions in acetonitrile in the presence of DBU (Scheme 1). Unfortunately, the reaction produced simply biscoumarin compounds 4a instead of the expected furocoumarins. [11] This might be because of the highly reactive 4-hydroxycoumarin, which undergoes Michael addition to the Knoeveagal condensed product [A] before the

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P. BORAH, P. S. NAIDU, AND P. J. BHUYAN expected attack of the pyridinium ylide forms in the reaction process (Scheme 1). In fact, formation of such biscoumarin is well precedented. [12] Then, we planned to utilize 3-aminoalkyl-4-hydroxycoumarins 6 with pyridinium salts 3 to achieve the furan fused coumarin derivatives 7 (Scheme 2). The 3-aminoalkyl-4-hydroxycoumarin derivative 6a was first prepared from onepot, three-component reaction of 4-hydroxycoumarin 1, benzaldehyde 2a, and pyrrolidine 5a in ethanol at room temperature following the reported method. [13] Interestingly, when the compound 6a so obtained was reacted with pyridinium salt 3a in the presence of a catalytic amount of DBU in ethanol under refluxing conditions, it afforded the dihydrofuro[2,3-c]coumarin derivative 7a in very good yield (Scheme 2). The structure of the compound was ascertained from the spectroscopic data and elemental analysis. The 1 H NMR spectra showed the absence of the singlet peak at d 5.23 and presence of two doublets at d 4.72 (J ¼ 4.86 Hz) and d 6.10 (J ¼ 6.96 Hz), which indicate the formation of cyclized dihydro furan fused product. The coupling constants of the 1 H NMR spectra of these two protons further indicate

SYNTHESIS OF DIHYDROFUROCOUMARIN DERIVATIVES 1535
the formation of the thermodynamicly stable trans isomer of the product. The mass spectra showed a sharp molecular ion peak at 369.3 (M þ H) þ . Then, we utilized a number of 3-aminoalkyl-4-hydroxy-coumarins 6 with various pyridinium salts bearing COPh, CN, and COOEt groups and synthesized a large number of dihydrofuro[2,3-c]coumarin derivatives 7b-i. All the new products obtained were characterized from their spectroscopic data and elemental analysis. Our observations are recorded in Table 1.
The reaction was also studied in some other solvents, for example, ethanol, tetrahydrofuran (THF), dimethylformamide (DMF), and toluene, but acetonitrile was found as the best solvent for the reaction. DBU was used as base in the reaction process for its nonnucleophilic nature. We studied the reaction by utilizing various aryl aldehydes possessing electron-withdrawing as well as electron-donating groups at the aromatic ring. It was observed that the reactions were smooth in all the cases. However, the aldehyde having the electron-withdrawing substituent produced the product in shorter time with better yield in comparison to the aldehyde with electron-donating substituent. Further increase in the reaction time did not improve the yield of the products.
It was very interesting to note that when salicylaldehyde 8a was used with 4-hydroxycoumarin 1a and pyrolidine 5a, we obtained the cyclized pyrano[2,3-c]coumarin derivative 9a instead of 3-aminoalkyl-4-hydroxycoumarins 6, in good yield (Scheme 3). Notably, pyran-fused coumarins are very important class of naturally occurring bioactive molecules. [14] The structure of the compound was ascertained from spectroscopic data and elemental analysis. Although the formation of a pyran ring was obvious because of the presence of two suitably located hydroxyl groups, notable point is that the cyclization occurred at very mild condition. Subsequently, a series of pyrano[3,2-c]coumarins 9b-l were synthesized by utilizing different substituted salicylaldehydes 8a-c with 4-hydroxycoumarin 1a,b and 5a,b and characterized. The number of generalizations is shown in Table 2. However, unlike the previous reaction, we have not observed any significant effect of substituent in the aromatic ring of the aldehyde in this reaction in terms of yield and reaction time.
The possible mechanism which could account for the formation of products 7a and 9a is depicted in Schemes 4 and 5.
The In conclusion, we have reported an efficient method for the synthesis of dihydrofurocoumarin derivatives starting from the reaction of 3-aminoalkyl-4-hydroxycoumarin and pyridinium ylides generated in situ from pyridinium salt. Moreover, a series of novel pyrano[3,2-c]-coumarin derivatives were synthesized via one-pot, threecomponent reaction of 4-hydroxycoumarin, aryl aldehydes, and secondary amines at room temperature. This reaction protocol can be explored for the synthesis of some other furan-fused heterocyclic compounds.

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P. BORAH, P. S. NAIDU, AND P. J. BHUYAN flask containing ethanol. Then the reaction mixture was stirred vigorously at room temperature for 3 h. After completion of the reaction (monitored by TLC), the solid compound was filtered off and crude products were recrystallized from ethanol. The product 9a was obtained in 73% yield. The structure of the compound was ascertained from the spectroscopic data and elemental analysis. Similarly, other compounds 9b-l were synthesized and characterized.

FUNDING
The authors thank the Department of Science and Technology (DST) and the Council for Scientific and Industrial Research (CSIR), New Delhi, for financial support (Project No. SR=S1=OC-24=2012 and Project CAAF-NE respectively). P. S. N. thanks the University Grants Commission for financial support.

SUPPORTING INFORMATION
Full experimental details and 1 H and 13 C NMR spectra of 7a, 7b, 7c, and 9a can be accessed on the publisher's website.