International Journal of Organic Chemistry
Vol. 2  No. 1 (2012) , Article ID: 17856 , 5 pages DOI:10.4236/ijoc.2012.21008

Stereoselective Synthesis of cis-Substituted-3’-anilino-2’, 3’-dihydro-4-2’-benzo[b]furanylcoumarins via Intramolecular Aldol Reactions

Lokesh A. Shastri1, Samundeeswari L. Shastri1, Manohar V. Kulkarni1*, Vivek K. Gupta2, Sanjeev Goswami2

1P. G. Department of Chemistry, Karnatak University, Dharwad, India

2P. G. Department of Physics, University of Jammu, Jammu Tawi, India

Email: *

Received December 12, 2011; revised January 24, 2012; accepted February 9, 2012

Keywords: Aldol Reaction; Stereoselective; Intramolecular; Mild Base; 4-Bromomethylcoumarins; Dihydrobenzofurans


The present study reports the reaction of 4-bromomethylcoumarins with salicylidineaniline in acetone with two equivalents of potassium carbonate resulted in the formation of title compounds at room temperature via intramolecular aldolization. The obtained compound is thermodynamically and kinetically stable with highly stereoselective and excellent yield.

1. Introduction

The 2,3-dihydrobenzofuran skeleton has been associated with diverse biological activities and natural occurrence [1-3]. A variety of coumarin derivatives with substitution at C4 have been found to exhibit anti-coagulant [4], antimicrobial [5] and anti-tumour [6] activity. The dihydrobenzofuranols has recently received considerable attention since they have been shown to possess antimicrobial activity [7]. Some of the structurally similar compounds 1 [8-12] used as drugs for the treatment of vitiligo and are claimed to be potent coronary vasodilatators, and plant growth regulating substance.

The new synthetic methods have been extensively investigated [13-18]. Inter and intra-molecular cyclisation reactions play an important role in the construction of dihydrobenzofurans. The intramolecular reaction of carbon nucleophiles with an electrochemically generated intermediate can provide a unique means for generating new carbon-carbon bonds, and this may also be used to generate a reactive intermediate to construct the dihydrobenzofuran skeletons under mild conditions [19]. Similarly proline catalyzed aldol reaction plays an important role as carbon-carbon bond formation 2 [20-23] Further mechanistic studies, that is Nitrones undergo deoxygenative reductive coupling and subsequent cyclisation to 3 [24]. Hence carbon nucleophiles are generally unstable under electro-oxidative conditions because most of the nucleophiles possess electron-rich heteroatoms or aromatic rings. Therefore the electrolytic potential is limited to the lower of those of the co-existing nucleophiles and those of the products [25]. On the other hand, it is difficult to construct the corresponding dihydrobenzofuranols directly by the [3 + 2] cycloaddition of unactivated alkenes with hydroxy aldehydes. In fact, the direct intermolecular attack of aliphatic alkenes has not been accomplished even when they were added to the reaction mixture in excessive amounts [26]. Hence only few methods are reported for the synthesis of stereo specifically enriched dihydrobenzofurans [27]. Although there are several photochemical approaches available for the synthesis of the dihydrobenzofuranol skeleton [28- 34]. All the methods yield trans and cis products.

In our earlier efforts the mild base catalysed formation of benzofuranyl coumarins were obtained as an desired product in the generation of carbanion via intramolecular cyclisation across the carbonyl carbon [35]. In continuation of our recent investigations in asymmetric synthesis towards the bioactive natural products, we have reported a mild base catalyzed asymmetric intramolecular cis aldolization affording various 3’-hdroxy-2’,3’-dihydro-4-2’- benzo[b]furanyl coumarins 4 (Figure 1) [36].

2. Results and Discussions

Here in we wish to report a mild base catalyzed asymmetric intramolecular cis aldolization and affording various 3’-Anilino-2’,3’-dihydro-4-2’-benzo[b]furanyl cou-

Figure 1. 2, 3-dihydrofurans.

marins (Scheme 1). Initially we studied several solvents with potassium carbonate catalyst (2 eq.) at refluxing temperature to find the necessary reaction condition for the cyclisation of desired product, but we briefly examined the synthetic experimental condition of these reaction of 5 with 6 (Scheme 1) afforded pure product 8 which we have earlier reported15 by dehydration to benzofuran. Then we carried out at room temperature to find appropriate reaction conditions for the cyclisation of the 5 with 6 to favor the desired dihydrobenzofurans 7. The acetone as solvent gave the best results (approximately more than 80% yields) in an excellent yield with single product, after simple purification by column chromatography by using ethyl hexane: purification by column chromatography by using hexane: ethyl acetate (7:3) (Table 1). The

Scheme 1. R = 6-CH3, 7-CH3, 6-Cl, 6-OCH3, R1 = H, 4-CH3, 3-Cl.

Table 1. The Physical data of 3’-anilino-2’,3’-dihydro-4-2’-benzo[b]furanylcoumarins (7a-l).

purified compound showed two characteristic doublets around δ 5.2 and 58 ppm. After the adjustment of the reaction parameters, several salicylidineaniline 6 and 4- bromomethyl coumarin 5 could be transformed cisselectively into the corresponding 3’-Anilino-2’,3’-dihydro-4-2’-benzo[b] furanylcoumarins 7a-l (Scheme 1, Table 1). The product 7 could be obtained with decreased yield (55% - 60%) by using solvents such as DMF, 1, 4-dioxane and ethanol.

However, a various 4-bromomethyl coumarins 5 [37] and substituent salicylidineaniline 6 could be cyclized with increased stereoselective products and short reaction time. The reaction to yield the 3’-Anilino-2’,3’-dihydro- 4-2’-benzo[b]furanylcoumarins 7a-l showed a full conversion after sixteen hours at room temperature, but a much longer reaction time of more than 30 hours, probably the elimination of aromatic amines starts due to the aromatisation of product 7 to 8 was observed (Scheme 1). The absolute configuration of the 3’-Anilino-2’,3’-dihydro- 4-2’-benzo[b]furanyl coumarins 7 was assigned by X-ray structure analysis of 7j to be 2R,3S (Figure 2). The cis selectivity of the product was further confirmed by comparison of the coupling constants of the methine protons in the 1H NMR spectra. The coupling constant was found to be 3.3 Hz, which indicates the cis configuration of the ring.

3. Conclusion

In conclusion, we accomplished the synthesis of title compound 3’-Anilino-2’,3’-dihydro-4-2’-benzo[b]furanyl coumarins derivatives through a combination of 5 and 6 strategy reaction by intramolecular aldol reaction affording cis-selectively using mild base potassium carbonate and this can be used for new method for stereoselective synthesis of substituted amino dihydrobenzofurans.

4. Experimental

Melting points were determined by using open capillary method and are uncorrected. IR spectra were recorded on a Nicolet-impact—410 FT infrared spectrometer. The NMR was recorded on a Bruker 300 MHz FT NMR spectrometer. 1H and 13C Chemical shift were represented as δ-values relative to the internal standard, tri-methylsilane. LC-MS spectra were recorded on MPS-SCIEXAPI-2000. The 4-bromomethylcoumarin 5 was prepared according to our earlier report. Salicyaldehyde and substituted aromatic amines were commercially available and used after purification. All reaction were carried out under nitrogen atmosphere.

Typical experimental Procedure for the Preparation of 3’-Anilino-2’,3’-dihydro-4-2’-benzo [b] furanylcoumarins (7a-l). A mixture of anhydrous potassium carbonate (700 mg, 0.005 mol) and salicylidineaniline (6) (500 mg,

Figure 2. X-ray structure of 7j: CCDC contains the supplementary crystallographic data for this paper. These data can be obtained free of charge at [or from the Cambridge Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK.

0.002 mol) was stirred for about half an hour in dry acetone (20 mL). To this 4-bromomethyl coumarins (5) (600 mg, 0.002 mol) were added and the stirring was continued for 16 - 18 h at room temperature. The mixture was diluted with crushed ice. Separated solid was filtered and washed with water, then washed with dilute HCl (1:1) and then with water. The residual solid was purified by silica gel column chromatography using hexane-ethyl acetate (7:3) afforded 720 mg (82%) or purified by crystallization using ethanol afforded less than 60%. (7a). IR (KBr) 1720, 3358 cm–1; 1H NMR (DMSO-d6) δ 2.46(s, 3H, 6-CH3 of coum), 4.24(s, 1H, NH), 5.24(d, 1H, C3-H, J = 3.3 Hz), 5.82(d, 1H, C2'-H, J = 3.3 Hz), 6.45(s, C3-H of coum), 6.69 - 7.67(m, 12H, Ar-H); 13C-NMR (300 MHz) δ 21.87, 61.24, 84.97, 108.63, 110.77, 112.02, 114.52, 117.61, 118.70, 121.14. 122.42, 125.54, 126.78, 128.52, 130.12, 130.57, 146.00, 148.58, 154.25, 156.56, 159.64, 161.89, MS (LCMS), m/z 369, 276 (base peak).

5. Acknowledgements

The authors acknowledge the Karnatak University for provided research facility and very grateful for University Grants Commission (UGC), and DST, New Delhi, for financial support.


  1. A. A. Ali, M. H. Mohamed, M. S. Kamel and M. A. Fouad, “Spring Studies on Securigera securidacea (L.) Deg. Dorfl. (Fabaceae) Seeds, an Antidiabetic Egyptian Folk Medicine,” Pharmazie, Vol. 53, 1998, pp. 710-715.
  2. K. Kataoka, T. Shiota, T. Takumi, T. Minoshima, W. Kenzo, T. Hiroko, M. Tsutomu, T. Keiko, O. Mikio, T. Hirofumi and Y. Hisao, “Potent Inhibitors of Acyl-CoA: Cholesterol Acyltransferase. 2. Structure-Activity Relationships of Novel N-(2,2-Dimethyl-2,3-dihydro-benzofuran-7-yl)amides,” Journal of Medicinal Chemistry, Vol. 39, No.8, 1996, pp. 1262-1270. doi:10.1021/jm950828+
  3. P. M. Aaron, R. W. Steve, M. L. Danuta, B. W. David, L. N. David, S. B. Elaine and E. N. David, “Dihydrobenzofuran Analogues of Hallucinogens. 4.1 Mescaline Derivatives,” Journal of Medicinal Chemistry, Vol. 40, No. 19, 1997, pp. 2997-3008. doi:10.1021/jm970219x
  4. U. Bhoga, “A New Synthetic Approach to Enantiomerically Enriched Dihydrobenzofurans: Use of a Hydrolytic Kinetic Resolution and an Intramolecular Epoxide Ring Opening Protocol Using 1-Benzyloxy-2-oxiranylmethylbenzenes,” Tetrahedron Letters, Vol. 46, No. 31, 2005, pp. 5239-5242. doi:10.1016/j.tetlet.2005.04.120
  5. S. H. Shrikant, V. K. Manohar and D. P. Vemanna, “Synthesis and Biological Activity of 4-(Sulphona Midomethyl) Coumarins,” Indian Journal of Chemistry, Vol. 24 B, 1985, pp. 459-461.
  6. J. G. Finn, E. Kenealy, S. Creaven and D. S. Egan, “In Vitro Cytotoxic Potential and Mechanism of Action of Selected Coumarins, Using Human Renal Cell Lines,” Cancer Letters, Vol. 183, No. 1, 2002, pp. 61-68. doi:10.1016/S0304-3835(02)00102-7
  7. S. A. Khanum, S. Shashikanth, B. S. Sudha and S. N. Sriharsha, “Photochemical Synthesis, and Antimicrobial Activity of Dihydrobenzofuranols from 2-Alkoxy Substituted Benzophenones and Ethyl-2-Aroyl Aryloxy Acetates,” Journal of Chemical Research, Vol. 8, 2003, pp. 463-464. doi:10.3184/030823403103174830
  8. Z. Yefen, L. Mercedes and B. S. Barry, “Synthesis of 2, 3-Dihydro-3-hydroxy-2-hydroxylalkylbenzofurans from Epoxy Aldehydes. One-Step Syntheses of Brosimacutin G, Vaginidiol, Vaginol, Smyrindiol, Xanthoarnol, and Avicenol A. Biomimetic Syntheses of Angelicin and Psoralen,” Journal of Organic Chemistry, Vol. 70, No. 5, 2005, pp. 1761-1770. doi:10.1021/jo047974k
  9. L. John, H. Svend and T. Ole, “Dihydrofurocoumarin Glucosides from Angelica Archangelica and Angelica Silvestris,” Phytochemistry, Vol. 22, No. 2, 1983, pp. 553- 555. doi:10.1016/0031-9422(83)83044-1
  10. J. Benedicto, C. G. Maria, A. Josefa, T. Pascual and G. Manuel, “Coumarins from Ferulago capillaris and F. Brachyloba,” Phytochemistry, Vol. 53, No. 8, 2000, pp. 1025-1031. doi:10.1016/S0031-9422(99)00524-5
  11. D. G. Bishan, K. B. Sunil and K. L Hand, “Alkaloids and coumarins of Heracleum wallichii,” Phytochemistry, Vol. 15, No. 4, 1976, pp. 576-576. doi:10.1016/S0031-9422(00)88988-8
  12. S. Hiroko, S. Yutaka, N. Hiroyuki and K. J. Yoko, “Plant Growth Regulators from Heracleum Lanatum,” Phytochemistry, Vol. 21, No. 9, 1982, pp. 2213-2215. doi:10.1016/0031-9422(82)85180-7
  13. Y. Kwase, S. Yamaguchi, S. Kondo and K. Shimokawa, “The Synthesis of dl-5-Acetyl-2-(1-hydrxymethylvinyl)- 2,3-dihydrobenzofuran and Its Esters,” Chemistry Letters, Vol. 7, No. 3, 1978, pp. 253-254. doi:10.1246/cl.1978.253
  14. H. Takahiro, U. Tetsuyuki and S. Murahashi, “Ichi. Palladium(II)-Catalysed Oxidative Cyclisation of 2-Allylphenols in the Presence of Copper(II) Acetate and Molecular Oxygen. Oxidation State of Palladium in the WackerType Reaction,” Journal of the Chemical Society, Chemical Communications, No. 11, 1979, pp. 475-476.
  15. R. Rastogi, G. Dixit and K. Zutshi, “Electrochemical Synthesis of Benzofuroxan: Role of Electrogenerated Iodonium Ion in the Intramolecular Cyclization of 2-Nitroaniline,” Electrochimica Acta, Vol. 29, No. 10, 1984, pp. 1345-1347. doi:10.1016/0013-4686(84)87008-5
  16. B. Raymond, G. C. Nigel, R. H. Guy, H. B. W. Stanley and H. Jordan, “Stereoselective Synthesis of the Dihydrobenzo[b]furan Segments of the Ephedradine Alkaloids,” Journal of the Chemical Society, Chemical Communications, No. 14, 1987, pp. 1102-1104.
  17. M. A. Huffman and L. S. Liebeskind, “Nickel(0)-Catalyzed Synthesis of Substituted Phenols from Cyclobutenones and Alkynes,” Journal of the American Chemical Society, Vol. 113, No. 7, 1991, pp. 2771-2772. doi:10.1021/ja00007a072
  18. S. Olivero, J. C. Clinet and J. C. E. Dunach, “Electrochemical Intramolecular Reductive Cyclisation Catalysed by Electrogenerated Ni(cyclam)2,” Tetrahedron Letters, Vol. 36, No. 25, 1995, pp. 4429-4432. doi:10.1016/0040-4039(95)00782-8
  19. K. Chiba, M. Fukuda, S. Kim, Y. Kitano and M. Ta da, “Dihydrobenzofuran Synthesis by an Anodic [3 + 2] Cycloaddition of Phenols and Unactivated Al Kenes,” Journal of Organic Chemistry, Vol. 64, No. 20, 1999, pp. 7654-7656. doi:10.1021/jo9908243
  20. R. Mahrwald, “Diastereoselection in Lewis-Acid-Mediated Aldol Additions,” Chemical Reviews, Vol. 99, No. 5, 1999, pp. 1095-1120. doi:10.1021/cr980415r
  21. R. Mahrwald, “Modern Aldol Reactions,” Wiley-VCH, Weinheim, 2004. doi:10.1002/9783527619566
  22. C. Palomo, M. Oiarbide and J. M. Garcia, “Current Progress in the Asymmetric Aldol Addition Reaction,” Chemical Society Reviews, Vol. 33, No. 2, 2004, pp. 65-75. doi:10.1039/b202901d
  23. D. Enders, O. Niemeier and L. Straver, “Asymmetric Organocatalytic Synthesis of cis-Substituted-Dihydrobenzofuranols via Intramolecular Aldol Reactions,” Synlett, No. 20, 2006, pp. 3399-3402. doi:10.1055/s-2006-956454
  24. J. Arumugasamy and L. Yong-Chien, “Indium-Mediated Tandem Dimerization and Cyclization of Nitrqones and Aldimines to 3-Arylaminodihydrobenzofurans under Aqueous Conditions,” Tetrahedron Letters, Vol. 42, No. 25, 2001, pp. 4361-4362. doi:10.1021/jo980601x
  25. J. Yoshida, M. Sugawara, M. Tatsumi and N. Kise, “Electrooxidative Interand Intramolecular Carbon-Carbon Bond Formation Using Organothio Groups as Electroauxiliaries,” Journal of Organic Chemistry, Vol. 63, No. 17, 1998, pp. 5950-5961.
  26. M. L. Kerns, S. M. Conroy and J. S. Swenton, “Dihydrobenzofuran Derivatives via the Anodic Cycloaddition Reaction of p-Methoxyphenols and Vinyl Sulfides,” Tetrahedron Letters, Vol. 35, No. 41, 1994, pp. 7529-7532. doi:10.1016/S0040-4039(00)78335-3
  27. U. Bhoga, “A New Synthetic Approach to Enantiomerically Enriched Dihydrobenzofurans: Use of a Hydrolytic Kinetic Resolution and an Intramolecular Epoxide Ring Opening Protocol Using 1-Benzyloxy-2-oxiranylmethylbenzenes,” Tetrahedron Letters, Vol. 46, No. 31, 2005, pp. 5239-5242. doi:10.1016/j.tetlet.2005.04.120
  28. S. P. Pappas, D. Z. Robert and E. A. James, “On Vicinal H-H Coupling Constants in 3-Hydroxy-2,3-dihydrobenzofuran Derivatives,” Journal of Heterocyclic Chemistry, Vol. 7, No. 5, 1970, pp. 1215-1217. doi:10.1002/jhet.5570070541
  29. E. M. Sharshira, S. Shimada, M. O. E. Hasegawa and T. Horaguchi, “Photocyclization reactions. Part-5. Synthesis of Dihydrobenzofuranols Using Photocyclization of 2- Alkoxybenzophenones and Ethyl 2-Benzoylphenoxyacetates,” Journal of Heterocyclic Chemistry, Vol. 33, 1996, pp. 1797-1805. doi:10.1002/jhet.5570330641
  30. P. J. Wagner, M. A. Meador and B. S. Park, “The Photocyclization of O-Alkoxy Phenyl Ketones,” Journal of the American Chemical Society, Vol. 112, No. 13, 1990, pp. 5199-5211. doi:10.1021/ja00169a031
  31. P. J. Wagner and J. S. Jang, “Lifetimes of 1,5-Biradicals Formed from Triplet O-Alkoxy Ketones,” Journal of the American Chemical Society, Vol. 115, No. 17, 1993, pp. 7914-7915. doi:10.1021/ja00070a062
  32. P. J. Wagner, M. A. Meador and J. C. Seaiano, “Photocyclizations of O-(Benzyloxy)acetophenone and -Benzophenone: Effects of Variable Rotational Freedom on Biradical Behavior,” Journal of the American Chemical Society, Vol. 106. No. 25, 1984, pp. 7988-7989. doi:10.1021/ja00337a066
  33. M. Abdul-Aziz, J. V. Auping and M. A. Meador, “Synthesis of Substituted-2,3,5,6-tetraarylbenzo[1,2,-b: 4,5-b'] Difurans,” Journal of Organic Chemistry, Vol. 60, No. 5, pp. 1303-1308. doi:10.1021/jo00110a038
  34. M. A. Meador and P. J. Wagner, “Photocyclization of Alpha. (O-Benzyloxyphenyl) Acetophenone: Triplet-State Epsilon-Hydrogen Abstraction,” Journal of Organic Chemistry, Vol. 50, No. 3, 1985, pp. 419-420. doi:10.1021/jo00203a038
  35. S. S. Hanmanthgad, V. D. Patil, V. D. Prakash, R. K. Dhruvaraj and V. M. Kulkarni, “Synthesis and Pharmacological Properties of Same 4, 2’-[Benzo(b)furanyl] Coumarins,” Indian Journal of Chemistry, Vol. 25B, 1986, pp. 779-781.
  36. L. A. Shastri, M. V. Kulkarni, V. K. Gupta and S. Goswami, “First Thermal Chemoselective Synthesis of Novel 20,30-Dihydro-30-Hydroxybenzo Furanylcoumarins,” Synthetic Communications, Vol. 38, 2008, pp. 1407-1415. doi:10.1080/00397910801914251
  37. M. V Kulkarni and V. D. Patil, “Studies on Coumarins,” Arch Pharm. (Weinheim), Vol. 314, 1981, pp. 708-711. doi:10.1002/ardp.19813140810


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