Logo Beilstein Institut

Tandem aldehyde–alkyne–amine coupling/cycloisomerization: A new synthesis of coumarins

  1. ,
  2. and
Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow-226 001, India, Fax: +91-(522)-2623405, Tel: +91–(522)–2612 411, Extn: 4379
  1. Corresponding author email
Associate Editor: P. R. Hanson
Beilstein J. Org. Chem. 2013, 9, 180–184. https://doi.org/10.3762/bjoc.9.21
Received 23 Oct 2012, Accepted 28 Dec 2012, Published 28 Jan 2013
Full Research Paper
cc by logo
PDF
Album
Supp Info
Cite

Abstract

Cu-catalyzed A3 coupling of ethoxyacetylene, pyrrolidine and salicylaldehydes led to a concomitant cycloisomerization followed by hydrolysis of the resultant vinyl ether to afford coumarins in a cascade process. The reaction proceeded through exclusive 6-endo-dig cyclization and is compatible with halo and keto groups giving coumarins in good to moderate yields.

Keywords: A3 coupling; cooperative catalysis; coumarin synthesis; cycloisomerization; transition-metal catalysts

Introduction

An alkyne, an aldehyde and an amine coupling, referred to as A3 coupling [1], has been found as an efficient method for C–N and C–C bond formation that results in equivalence of reductive alkylation of amines while at the same time appending an alkyne, i.e., a highly useful moiety for further functionlization. This three-component coupling has been accomplished with a very broad range of transition metals, including copper, silver, gold, ruthenium/copper, cobalt, iridium and iron. Similarly, cycloisomerization of alkynols and alkynamines has also been an attractive approach for the synthesis of various known and new heterocyclic frameworks [2-22]. Various alkynophilic catalysts such as transition-metal catalysts (based on gold, mercury, platinum, silver, etc.), Brønsted acids and electrophilic iodine sources (I2, ICl, NIS) have been used for the transformation.

If one of the partners in A3 coupling has any nucleophile for concomitant electrophilic cyclization on the alkyne group in the A3 product, this may result in an interesting reaction sequence to produce various heterocycles. Recently, Gevorgyan and co-workers [23] used these two processes (A3/5-exo-dig cycloisomerization) in tandem to obtain indolines, which were then converted to useful substituted indole derivatives (Scheme 1, (a)). Similarly, Patil and Raut [24] reported an elegant method for the synthesis of 2-substituted quinolines from 2-aminobenzaldehydes and terminal alkynes by a tandem A3/6-endo-dig-cycloisomerization (Scheme 1, (b)) using a cooperative catalytic system consisting of CuI and pyrrolidine. Prior to these two findings, Sakai et al. [25] reported a facile synthesis of 3-aminobenzofurans through an A3 coupling and an exclusive 5-exo-dig-cycloisomerization (Scheme 1, (c)). Similarly, Yan and Liu [26], Fujii et al. [27,28], Chernyk and Gevorgyan [29], Ji et al. [30], and Wu et al. [31] reported the synthesis of aminoindolizines, 2-(aminomethyl)indoles, imidazopyridines, butenolides and 1,2-dihydroisoquinoline derivatives, respectively, combining these two approaches successfully. Along the same lines, we investigated a reaction between ethoxyacetylene, pyrrolidine and salicylaldehyde in the presence of a transition-metal catalyst. That, after consecutive A3 coupling, cycloisomerization and hydrolysis of the resultant vinyl ether intermediate, should produce coumarins (Scheme 1, (d)). The reason for the selective 6-endo-dig cyclization of such a cooperative-catalysis reaction has been well documented through DFT computational studies by Patil et al. in their recent publication [32].

[1860-5397-9-21-i1]

Scheme 1: Synthesis of various heterocycles by a tandem A3 coupling/cycloisomerization strategy.

Results and Discussion

Coumarins [33-46] have been attractive targets [47-53] for synthetic chemists due to their frequent occurrence in nature and for their interesting biological and pharmaceutical applications. In continuation of our interest in the cycloisomerization of alkynols and alkynamines for the synthesis of various heterocycles [17-22], we herein report the synthesis of coumarins from salicylaldehydes by a Cu-catalyzed exclusive 6-endo-dig electrophilic cyclization of the intermediate hydroxyphenylpropargylamine as shown in Scheme 1 (d). We initially investigated the reaction with various Cu-, Au- and Pd-based catalysts in the presence of pyrrolidine in MeCN at room temperature (Table 1).

Table 1: Catalyst and condition screening.

[Graphic 1]
entry catalyst solvent/temp base Time (h) yield (%)
1 CuI CH3CN/rt pyrrolidine 24 58
2 Cu(OTf)2 CH3CN/rt pyrrolidine 24 24
3 AuCl CH3CN/rt pyrrolidine 24 35
4 AuCl3 CH3CN/rt pyrrolidine 24 48
5 HAuCl4 CH3CN/rt pyrrolidine 24 50
6 PPh3AuCl CH3CN/rt pyrrolidine 24 30
7 PdCl2 CH3CN/rt pyrrolidine 24 25
8 CuI CH3CN/100 °C pyrrolidine 2 65
9 — CH3CN/100 °C pyrrolidine 3 —
10 CuI CH3CN/100 °C pyrrolidine 3 —

The required product was obtained but in very low yield, and the reaction time was prolonged to more than 24 h. When the reaction temperature was raised to 100 °C in the presence of CuI and pyrrolidine in CH3CN, the desired product was obtained in 65% in 2 h.

Encouraged by this promising result, the scope of the reaction was tested with a number of salicylaldehydes. As is apparent from Table 2, the reaction is highly versatile, working efficiently with both electron-rich and -poor substrates. Substrates 1b–h with various alkyl substituents produced the corresponding coumarins 2b–h in 50–82% yield.

Table 2: Synthesis of coumarins 2 from salicylaldehydes 1 by A3 coupling/cycloisomerization.

[Graphic 2]
entry substrate 1a product 2 yield (%)b entry substrate 1a product 2 yield (%)b
1 [Graphic 3]
1a 		[Graphic 4]
2a 		62 9 [Graphic 5]
1i 		[Graphic 6]
2i 		62
2 [Graphic 7]
1b 		[Graphic 8]
2b 		68 10 [Graphic 9]
1j 		[Graphic 10]
2j 		62
3 [Graphic 11]
1c 		[Graphic 12]
2c 		78 11 [Graphic 13]
1k 		[Graphic 14]
2k 		60
4 [Graphic 15]
1d 		[Graphic 16]
2d 		75 12 [Graphic 17]
1l 		[Graphic 18]
2l 		65
5 [Graphic 19]
1e 		[Graphic 20]
2e 		80 13 [Graphic 21]
1m 		[Graphic 22]
2m 		76
6 [Graphic 23]
1f 		[Graphic 24]
2f 		82 14 [Graphic 25]
1n 		[Graphic 26]
2n 		65
7 [Graphic 27]
1g 		[Graphic 28]
2g 		50 15 [Graphic 29]
1o 		[Graphic 30]
2o 		84
8 [Graphic 31]
1h 		[Graphic 32]
2h 		80        

aAll reactions were conducted with 1 mmol substrate in 0.25 M concentration. bIsolated yields.

A slight reduction in yield was observed in the cases of halogen containing substrates. Thus, substrates 1i–l gave the required products 2i–l in 62–65% yield. Substrates 1m and 1n with extended conjugation also reacted well under the standardized conditions to give the corresponding products 2m and 2n in good yields (65–76%). The reaction is highly compatible with keto functionality, as is evident from the conversion of 1o to 2o in 84% yield. It should be noted that the reaction is limited to aldehydes and not to ketones, which do not undergo A3 coupling.

A plausible mechanism via a cooperative catalysis by Cu and pyrrolidine is described in Scheme 2 (with the assistance of the work reported by Patil et al. [24,32]). Initial condensation of pyrrolidine with salicylaldehyde 1 produced iminium intermediate A. The addition of copper ethoxyacetylide, formed on the reaction of ethoxyacetylene with Cu, to the iminium intermediate A yielded propargylamine intermediate B. Copper being coordinated with the amine group immediately activated the alkyne group to facilitate cycloisomerization with the phenoxy group, to produce vinyl ether C, which, being susceptible to hydrolysis, underwent water addition followed by an extrusion of the pyrrolidine molecule for further catalysis. The resulted intermediate D lost an EtOH molecule to furnish the required product 2.

[1860-5397-9-21-i2]

Scheme 2: A plausible mechanistic pathway.

Conclusion

In summary, a facile synthesis of coumarins is reported from readily available starting materials, i.e., salicylaldehydes and ethoxyacetylene, through a tandem A3 coupling and cycloisomerization cascade. The reaction was catalyzed by a pyrrolidine and copper iodide cooperative catalytic system, and the reaction was not observed in the absence of either of the catalysts. The yields are good to moderate and the reaction has a good substrate scope being compatible with halogen and keto groups. The process constitutes an easy and efficient access to highly valuable building blocks of natural products or biologically active compounds.

Supporting Information

Supporting Information File 1: Experimental procedures and product characterization for compounds 2a–o.
Format: PDF Size: 3.9 MB Download

Acknowledgments

We thank CSIR for the financial aid and Prof. Pierre Deslongchamps, emeritus professor at University of Laval, Canada, and Dr. T. K. Chakraborty, Director CSIR-CDRI for their constant encouragement. We thank SAIF division CDRI for the analytical data support. Generous financial aid from CSIR Network project "BSC0102" (CSIR-CDRI-THUNDER) is acknowledged. CDRI Communication NO. 8371.

References

  1. Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V. Chem. Soc. Rev. 2012, 41, 3790. doi:10.1039/c2cs15356d
    Return to citation in text: [1]
  2. Mothe, S. R.; Kothandaraman, P.; Lauw, S. J. L.; Chin, S. M. W. C.; Chan, P. W. H. Chem.–Eur. J. 2012, 18, 6133. doi:10.1002/chem.201200578
    Return to citation in text: [1]
  3. Inamoto, K.; Asano, N.; Nakamura, Y.; Yonemoto, M.; Kondo, Y. Org. Lett. 2012, 14, 2622. doi:10.1021/ol300958c
    Return to citation in text: [1]
  4. Tomás-Mendivil, E.; Toullec, P. Y.; Diez, J.; Conejero, S.; Michelet, V.; Cadierno, V. Org. Lett. 2012, 14, 2520. doi:10.1021/ol300811e
    Return to citation in text: [1]
  5. Kothandaraman, P.; Mothe, S. R.; Toh, S. S. M.; Chan, P. W. H. J. Org. Chem. 2011, 76, 7633. doi:10.1021/jo201208e
    Return to citation in text: [1]
  6. Mancuso, R.; Mehta, S.; Gabriele, B.; Salerno, G.; Jenks, W. S.; Larock, R. C. J. Org. Chem. 2010, 75, 897. doi:10.1021/jo902333y
    Return to citation in text: [1]
  7. Jiang, B.; Si, Y.-G. J. Org. Chem. 2002, 67, 9449. doi:10.1021/jo0204606
    Return to citation in text: [1]
  8. Gabriele, B.; Mancuso, R.; Salerno, G.; Lupinacci, E.; Ruffolo, G.; Costa, M. J. Org. Chem. 2008, 73, 4971. doi:10.1021/jo8006495
    Return to citation in text: [1]
  9. Hessian, K. O.; Flynn, B. L. Org. Lett. 2006, 8, 243. doi:10.1021/ol052518j
    Return to citation in text: [1]
  10. Chen, Y.; Cho, C.-H.; Larock, R. C. Org. Lett. 2009, 11, 173. doi:10.1021/ol8021287
    Return to citation in text: [1]
  11. Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2008, 130, 15720. doi:10.1021/ja805326f
    Return to citation in text: [1]
  12. Patil, N. T.; Kavthe, R. D.; Raut, V. S.; Shinde, V. S.; Sridhar, B. J. Org. Chem. 2008, 75, 1277. doi:10.1021/jo902293f
    Return to citation in text: [1]
  13. Nishizawa, M.; Imagawa, H.; Yamamoto, H. Org. Biomol. Chem. 2010, 8, 511. doi:10.1039/b920434b
    Return to citation in text: [1]
  14. Alcaide, B.; Almendros, P.; Alonso, J. M. Org. Biomol. Chem. 2011, 9, 4405. doi:10.1039/c1ob05249g
    Return to citation in text: [1]
  15. Huo, Z.; Gridnev, I. D.; Yamamoto, Y. J. Org. Chem. 2010, 75, 1266. doi:10.1021/jo902603v
    Return to citation in text: [1]
  16. Huo, Z.; Yamamoto, Y. Tetrahedron Lett. 2009, 50, 3651. doi:10.1016/j.tetlet.2009.03.129
    And the references therein.
    Return to citation in text: [1]
  17. Reddy, M. S.; Kumar, Y. K.; Thirupathi, N. Org. Lett. 2012, 14, 824. doi:10.1021/ol2033493
    Return to citation in text: [1] [2]
  18. Reddy, M. S.; Thirupathi, N.; Babu, M. H. Eur. J. Org. Chem. 2012, 5803. doi:10.1002/ejoc.201200782
    Return to citation in text: [1] [2]
  19. Reddy, M. S.; Thirupathi, N.; Kumar, Y. K. RSC Adv. 2012, 2, 3986. doi:10.1039/c2ra20213a
    Return to citation in text: [1] [2]
  20. Ravindar, K.; Reddy, M. S.; Deslongchamps, P. Org. Lett. 2011, 13, 3178. doi:10.1021/ol201102x
    Return to citation in text: [1] [2]
  21. Ravindar, K.; Reddy, M. S.; Lindqvist, L.; Pelletier, J.; Deslongchamps, P. J. Org. Chem. 2011, 76, 1269. doi:10.1021/jo102054r
    Return to citation in text: [1] [2]
  22. Ravindar, K.; Reddy, M. S.; Lindqvist, L.; Pelletier, J.; Deslongchamps, P. Org. Lett. 2010, 12, 4420. doi:10.1021/ol1019663
    Return to citation in text: [1] [2]
  23. Chernyak, D.; Chernyak, N.; Gevorgyan, V. Adv. Synth. Catal. 2010, 352, 961–966. doi:10.1002/adsc.201000015
    Return to citation in text: [1]
  24. Patil, N. T.; Raut, V. S. J. Org. Chem. 2010, 75, 6961. doi:10.1021/jo101103a
    Return to citation in text: [1] [2]
  25. Sakai, N.; Uchida, N.; Konakahara, T. Tetrahedron Lett. 2008, 49, 3437. doi:10.1016/j.tetlet.2008.03.111
    Return to citation in text: [1]
  26. Yan, B.; Liu, Y. Org. Lett. 2007, 9, 4323. doi:10.1021/ol701886e
    Return to citation in text: [1]
  27. Ohno, H.; Ohta, Y.; Oishi, S.; Fujii, N. Angew. Chem., Int. Ed. 2007, 46, 2295. doi:10.1002/anie.200604342
    Return to citation in text: [1]
  28. Ohta, Y.; Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2009, 74, 7052. doi:10.1021/jo901328q
    Return to citation in text: [1]
  29. Chernyk, N.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2743. doi:10.1002/anie.200907291
    Return to citation in text: [1]
  30. Zhang, Q.; Chang, M.; Hu, X. Y.; Li, B. G.; Ji, J. H. J. Am. Chem. Soc. 2010, 132, 7256–7257. doi:10.1021/ja101804p
    Return to citation in text: [1]
  31. Ye, Y.; Ding, Q.; Wu, J. Tetrahedron 2008, 64, 1378–1382. doi:10.1016/j.tet.2007.11.055
    Return to citation in text: [1]
  32. Patil, N. T.; Nijamudheen, A.; Datta, A. J. Org. Chem. 2012, 77, 6179. doi:10.1021/jo300949d
    Return to citation in text: [1] [2]
  33. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell Science Ltd: Oxford, 2006; p 170.
    Return to citation in text: [1]
  34. Dayam, R.; Gundla, R.; Al-Mawsawi, L. Q.; Neamati, N. Med. Res. Rev. 2008, 28, 118. doi:10.1002/med.20116
    Return to citation in text: [1]
  35. Thuong, P. T.; Hung, T. M.; Ngoc, T. M.; Ha, D. T.; Min, B. S.; Kwack, S. J.; Kang, T. S.; Choi, J. S.; Bae, K. Phytother. Res. 2010, 24, 101. doi:10.1002/ptr.2890
    Return to citation in text: [1]
  36. Kostova, I. Curr. Med. Chem. - Anti-Cancer Agents 2005, 5, 29. doi:10.2174/1568011053352550
    Return to citation in text: [1]
  37. Harris, E. B. J.; Banwell, M. G.; Willis, A. C. Tetrahedron Lett. 2011, 52, 6887. doi:10.1016/j.tetlet.2011.10.036
    Return to citation in text: [1]
  38. Murray, R. D. H. Nat. Prod. Rep. 1995, 12, 477. doi:10.1039/np9951200477
    Return to citation in text: [1]
  39. Estevez-Braun, A.; Gonzalez, A. G. Nat. Prod. Rep. 1997, 14, 465. doi:10.1039/np9971400465
    Return to citation in text: [1]
  40. Zorn, J. A.; Wille, H.; Wolan, D. W.; Wells, J. A. J. Am. Chem. Soc. 2011, 133, 19630. doi:10.1021/ja208350u
    Return to citation in text: [1]
  41. Gordo, J.; Avo, J.; Parola, A. J.; Lima, J. C.; Pereira, A.; Branco, P. S. Org. Lett. 2011, 13, 5112. doi:10.1021/ol201983u
    Return to citation in text: [1]
  42. Hamdi, N.; Saoud, M.; Romerosa, A. 4-Hydroxy Coumarine: a Versatile Reagent for the Synthesis of Heterocyclic and Vanillin Ether Coumarins with Biological Activities. In Topics in Heterocyclic Chemistry; Khan, M. T. H., Ed.; Topics in Heterocyclic Chemistry, Vol. 11; Springer Verlag: Heidelberg, 2007; pp 283–301. doi:10.1007/7081_2007_062
    Return to citation in text: [1]
  43. Reutrakul, V.; Leewanich, P.; Tuchinda, P.; Pohmakotr, M.; Jaipetch, T.; Sophasan, S.; Santisuk, T. Planta Med. 2003, 69, 1048. doi:10.1055/s-2003-45154
    Return to citation in text: [1]
  44. Marcu, M. G.; Chadli, A.; Bouhouche, I.; Catelli, M.; Neckers, L. M. J. Biol. Chem. 2000, 275, 37181. doi:10.1074/jbc.M003701200
    Return to citation in text: [1]
  45. Bras, G. L.; Radanyi, C.; Peyrat, J.-F.; Brion, J.-D.; Alami, M.; Marsaud, V.; Stella, B.; Renoir, J.-M. J. Med. Chem. 2007, 50, 6189. doi:10.1021/jm0707774
    Return to citation in text: [1]
  46. Radanyi, C.; Bras, G. L.; Messaoudi, S.; Bouclier, C.; Peyrat, J.-F.; Brion, J.-D.; Marsaud, V.; Renoir, J.-M.; Alami, M. Bioorg. Med. Chem. Lett. 2008, 18, 2495. doi:10.1016/j.bmcl.2008.01.128
    Return to citation in text: [1]
  47. Min, M.; Kim, B.; Hong, S. Org. Biomol. Chem. 2012, 10, 2692. doi:10.1039/c2ob07137a
    Return to citation in text: [1]
  48. Schmidt, B.; Krehl, S. Chem. Commun. 2011, 47, 5879. doi:10.1039/c1cc11347j
    Return to citation in text: [1]
  49. Audisio, D.; Messaoudi, S.; Brion, J.-D.; Alami, M. Eur. J. Org. Chem. 2010, 1046. doi:10.1002/ejoc.200901107
    Return to citation in text: [1]
  50. Upadhyay, P. K.; Kumar, P. Tetrahedron Lett. 2009, 50, 236. doi:10.1016/j.tetlet.2008.10.133
    Return to citation in text: [1]
  51. Yamamoto, Y.; Kirai, N. Org. Lett. 2008, 10, 5513. doi:10.1021/ol802239n
    Return to citation in text: [1]
  52. Jia, C.; Piao, D.; Kitamura, T.; Fujiwara, Y. J. Org. Chem. 2000, 65, 7516. doi:10.1021/jo000861q
    Return to citation in text: [1]
  53. Trost, B. M.; Toste, F. D.; Greenman, K. J. Am. Chem. Soc. 2003, 125, 4518. doi:10.1021/ja0286573
    Return to citation in text: [1]

© 2013 Reddy et al; licensee Beilstein-Institut.
This is an Open Access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (http://www.beilstein-journals.org/bjoc)

Other Beilstein-Institut Open Science Activities
Journal Logo
Institut Logo
Preprint Logo
Symposia Logo