Direct synthesis of α-aminophosphonates from biomass resources catalyzed by HReO4

Vera M. S. Isca and Ana C. Fernandes *
Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal. E-mail:; Fax: +351 218464455; Tel: +351 218419264

Received 28th April 2018 , Accepted 4th June 2018

First published on 5th June 2018

This work describes the one-pot conversion of xylose and xylan into a large variety of α-aminophosphonates with moderate to good overall yields and good chemoselectivity catalyzed by HReO4.


Conversion of biomass to value-added products provides a sustainable alternative to the current chemical industry that is predominantly dependent on fossil fuels. However, these processes typically afford chemicals containing only C, H, and O atoms. Nowadays, there is growing interest in the production of renewable chemicals that contain other heteroatoms, such as N and P, but their availability in the biomass resources limits the productivity of these compounds. For these reasons, the development of alternative strategies including the conversion of renewable O-containing chemicals into their nitrogen- and phosphorus-analogues can offer viable pathways for the more sustainable chemical and pharmaceutical industries.

α-Aminophosphonates are amino acid analogues, which have found a wide range of applications in the areas of industrial, agricultural, and medicinal chemistry owing to their biological and physical properties as well as their utility as synthetic intermediates. Additionally, aminophosphonates display a broad spectrum of activities including inhibition of enzymes1 such as synthase,2 HIV protease,3 rennin,4 phosphatase,5 and PTPases.6 They are also used as antibacterial,7 antiviral,8 antifungal,9 and antitumor agents,10 herbicides,11 plant regulators, and potent antibiotics,12 and in the antibody generation.13

A number of methods have been developed for the synthesis of α-aminophosphonates both in racemic and optically active forms.14–20 Several catalysts have been employed for the synthesis of α-aminophosphonates including SnCl2·2H2O,21 ZnBr2,22 HfCl4,23 lanthanide triflate,24 Yb(PFO)3,25 SmI2,26 TaCl5,27 BiCl3,28 LiClO4,29 FeCl3,30 MoO2Cl2[thin space (1/6-em)]31 and [CpRu(PPh3)2Cl].32 To the best of our knowledge, the one-pot synthesis of α-aminophosphonates from carbohydrates has never been reported.

In continuation of our work on the conversion of biomass resources into value-added compounds,33,34 here, we investigated the one-pot conversion of carbohydrates into a large variety of α-aminophosphonates catalyzed by HReO4 (Fig. 1).

image file: c8gc01343h-f1.tif
Fig. 1 One-pot conversion of carbohydrates into α-aminophosphonates catalyzed by HReO4.

Results and discussion

The conversion of carbohydrates into furfural has received great interest.35 In our previous work,34 we studied the conversion of carbohydrates into furfural using HReO4 as the catalyst. Furfural was obtained with 80% yield from xylose catalyzed by 5 mol% of HReO4 and with 56% yield from the polysaccharide xylan in the presence of 10 mol% of HReO4 at 140 °C using dioxane as the solvent (Fig. 2). Lower amounts of catalyst and lower temperatures also led to a decrease in the yield of furfural.
image file: c8gc01343h-f2.tif
Fig. 2 Conversion of xylose and xylan into furfural catalyzed by HReO4.

In this work, we investigated the one-pot synthesis of α-aminophosphonates from xylose by in situ reaction of furfural with several anilines and H-phosphonates (Fig. 3). This one-pot three reaction process was initially studied with 4-fluoroaniline and the H-phosphonates HP(O)(OEt)2, HP(O)(OMe)2, HP(O)(OBu)2 and HP(O)(OPh)2 (Table 1). The best yield (67%) was obtained in the presence of HP(O)(OEt)2 (Table 1, entry 1). The reactions with HP(O)(OMe)2 and HP(O)(OBu)2 (Table 1, entries 2 and 3) gave the α-aminophosphonates in a slightly lower yield (50%). Finally, the formation of α-aminophosphonate was not observed using the bulky HP(O)(OPh)2 (Table 1, entry 4).

image file: c8gc01343h-f3.tif
Fig. 3 One-pot synthesis of α-aminophosphonates from xylose catalyzed by HReO4.
Table 1 One-pot synthesis of α-aminophosphonates using different HP(O)(OR)2[thin space (1/6-em)]a

image file: c8gc01343h-u1.tif

Entry HP(O)(OR)2 Product Yieldb (%)
a The reactions were carried out with 1.0 mmol xylose, 1.0 mmol aniline and 1.2 mmol HP(O)(OR)2. b Isolated yields.
1 HP(O)(OEt)2 image file: c8gc01343h-u2.tif 67
2 HP(O)(OMe)2 image file: c8gc01343h-u3.tif 50
3 HP(O)(OBu)2 image file: c8gc01343h-u4.tif 50
4 HP(O)(OPh)2 image file: c8gc01343h-u5.tif 0

Due to the high importance of α-aminophosphonates, the one-pot synthesis of α-aminophosphonates from xylose catalyzed by HReO4 was explored using a large variety of anilines containing electron-donating and electron-withdrawing groups, producing the corresponding α-aminophosphonates with moderate to good overall yields (Table 2). In general, the reaction with anilines containing electron-withdrawing groups led to the formation of aminophosphonates with the best yields. In contrast, no reaction was observed using benzylamine, cyclohexylamine and cyclopropylaniline. This procedure was also tested with the secondary N-methylaniline in order to study the efficiency of this methodology for the synthesis of tertiary α-aminophosphonates. However, this reaction gave the α-aminophosphonates in only 30% yield after 3 h. Several functional groups were tolerated under the reaction conditions including –CO2Me, –CN, –SO2, –F, –CF3, –Br, and –Cl, showing the chemoselectivity of this novel method.

Table 2 One-pot synthesis of α-aminophosphonates from xylose catalyzed by HReO4[thin space (1/6-em)]a,b
a The reactions were carried out with 1.0 mmol xylose, 1.0 mmol aniline and 1.2 mmol HP(O)(OEt)2. b Isolated yields. c This reaction required 3 h after the addition of HP(O)(OEt)2.
image file: c8gc01343h-u6.tif

The catalytic activity of HReO4 (5 mol%) was also evaluated in the conversion of 1.0 g (6.7 mmol) of xylose with 4-fluoroaniline and HP(O)(OEt)2, giving the corresponding α-aminophosphonate in 40% yield after 3 h.

The possible use of the catalyst HReO4 in multiple cycles was also investigated in the conversion of xylose into α-aminophosphonates using 4-fluoroaniline and HP(O)(OEt)2, by successive additions of xylose, 4-fluoroaniline and HP(O)(OEt)2 to the reaction mixture, without separating the catalyst at the end of each cycle. The yield obtained for each catalytic cycle was determined by 1H NMR spectroscopy using mesitylene as the internal standard. The results showed that α-aminophosphonate was obtained in the second cycle with only 25% yield and in the third cycle no product formation occurred.

The synthesis of α-aminophosphonates as also explored from other pentoses such as ribose and arabinose catalyzed by a higher amount of HReO4 (10 mol%), using 4-fluoroaniline and HP(O)(OEt)2, producing only 26% and 17% yield, respectively. These low yields were due to the low conversion of these pentoses to furfural, as previously observed by other authors.36–38 For example, Garrett37 reported that the conversion rate of arabinose is lower than that of xylose, proposing that the steric positioning of the hydroxyl groups in the pentose is the control factor that leads to different reactivities. Dussan38 suggested that it is more difficult to dehydrate the α-pyranose tautomer, the predominant form of arabinose, than β-pyranose, the predominant form of xylose.

This novel method was also applied to the synthesis of α-aminophosphonates from the polysaccharide xylan, which is made from units of xylose and is found in plant cell walls and some algae. This chemical transformation involves one-pot four reactions, including the cleavage of xylan into xylose, promoted by the aqueous solution of HReO4 (Fig. 4).

image file: c8gc01343h-f4.tif
Fig. 4 One-pot synthesis of α-aminophosphonates from xylan catalyzed by HReO4.

A large variety of α-aminophosphonates were obtained from the reaction of xylan with different anilines and HP(O)(OEt)2 with moderate overall yields and good chemoselectivity (Table 3).

Table 3 One-pot synthesis of α-aminophosphonates from xylan catalyzed by HReO4[thin space (1/6-em)]a,b
a The reactions were carried out with 1.0 mmol xylan, 1.0 mmol aniline and 1.2 mmol HP(O)(OEt)2. b Isolated yields.
image file: c8gc01343h-u7.tif


This work reports the first methodology for the one-pot sustainable synthesis of α-aminophosphonates, compounds with important biological activities, from carbohydrates in moderate to good overall yields. This process allows the synthesis of compounds containing N and P atoms directly from biomass resources and provides a new strategy for the synthesis of heteroatom compounds from biomass resources.

Experimental section

General procedure for the one-pot synthesis of α-aminophosphonates

To a Schlenk flask equipped with a J. Young tap containing a solution of carbohydrate (1.0 mmol pentose) in 1,4-dioxane (5 mL) was added HReO4 (5–10 mol%). The reaction mixture was stirred in a closed Schlenk flask at 140 °C for 2 h. After cooling the reaction mixture to room temperature, aniline (1.0 mmol) and HP(O)(OEt)2 (1.2 mmol) were added and the mixture was stirred at 140° C for 1 h. Then, water (3.0 mL) was added and the mixture was stirred at 80 °C for 1 h. The reaction mixture was cooled to ambient temperature and extracted with ethyl acetate (2 × 10.0 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography with appropriate mixtures of n-hexane[thin space (1/6-em)]:[thin space (1/6-em)]ethyl acetate, affording the α-aminophosphonates.

Conflicts of interest

There are no conflicts to declare.


This research was supported by Fundação para a Ciência e Tecnologia through project UID/QUI/00100/2013. Vera Isca thanks FCT for grant and Ana Fernandes (IF/00849/2012) acknowledges FCT for the “Investigador FCT” Program. The authors also thank the Portuguese NMR Network (IST-UTL Center) for providing access to the NMR facilities.


  1. R. Hirschmann, A. B. Smith, C. M. Taylor, P. A. Benkovic, S. D. Taylor, M. Yager, P. A. Sprengler and S. J. Benkovic, Science, 1994, 265, 234–237 CrossRef PubMed.
  2. J. A. Sikorski, M. J. Miller, D. S. Braccolino, D. G. Cleary, S. D. Corey, J. L. Font, G. J. Kenneth, C. Y. Han, K. C. Lin, P. D. Pansegrau, J. E. Ream, D. Schnur, A. Shah and M. C. Walker, Phosphorus, Sulfur Silicon Relat. Elem., 1993, 76, 115–118 CrossRef.
  3. B. Stowasser, K.-H. Budt, L. Jian-Qi, A. Peyman and D. Ruppert, Tetrahedron Lett., 1992, 33, 6625–6628 CrossRef.
  4. D. V. Patel, K. Rielly-Gauvin and D. E. Ryono, Tetrahedron Lett., 1990, 31, 5587–5590 CrossRef.
  5. S. A. Beers, C. F. Schwender, D. A. Loughney, E. Malloy, K. Demarest and J. Jordan, Bioorg. Med. Chem., 1996, 4, 1693–1701 CrossRef PubMed.
  6. T. R. Bruke, J. J. Brachi, C. George, G. Wolf, S. E. Shoelson and X. Yan, J. Med. Chem., 1995, 38, 1386–1396 CrossRef.
  7. J. Grembecka, A. Mucha, T. Cierpicki and P. Kafarski, J. Med. Chem., 2003, 46, 2641–2655 CrossRef PubMed.
  8. J. Huang and R. Chen, Heteroat. Chem., 2000, 11, 480–492 CrossRef.
  9. L. Maier and P. J. Diel, Phosphorus, Sulfur Silicon Relat. Elem., 1994, 90, 259–279 CrossRef.
  10. G. Lavielle, P. Hautefaye, C. Schaeffer, J. A. Boutin, C. A. Cudennec and A. Pierre, J. Med. Chem., 1991, 34, 1998–2003 CrossRef PubMed.
  11. K. M. Yager, C. M. Taylor and A. B. Smith, J. Am. Chem. Soc., 1994, 116, 9377–9378 CrossRef.
  12. U. Groth, L. Lehmann, L. Richter and U. Schollkopf, Heterocycles, 1993, 4, 427–431 Search PubMed.
  13. R. Hirschmann, A. B. Smith, C. M. Taylor, P. A. Benkovic, S. D. Taylor, K. M. Yager, P. A. Sprengler and S. J. Benkovic, Science, 1994, 265, 234–237 CrossRef PubMed.
  14. G. D. Joly and E. N. Jacobsen, J. Am. Chem. Soc., 2004, 126, 4102–4103 CrossRef PubMed.
  15. D. Pettersen, M. Marcolini, L. Bernardi, F. Fini, R. P. Herrera, V. Sgarzani and A. Ricci, J. Org. Chem., 2006, 71, 6269–6272 CrossRef PubMed.
  16. B. Saito, H. Egami and T. Katsuki, J. Am. Chem. Soc., 2007, 129, 1978–1986 CrossRef PubMed.
  17. J. P. Abell and H. Yamamoto, J. Am. Chem. Soc., 2008, 130, 10521–10523 CrossRef PubMed.
  18. W. Xu, S. Zhang, S. Yang, L.-H. Jin, P. S. Bhadury, D.-Y. Hu and Y. Zhang, Molecules, 2010, 15, 5782–5796 CrossRef PubMed.
  19. M. Ohara, S. Nakamura and N. Shibata, Adv. Synth. Catal., 2011, 353, 3285–3289 CrossRef.
  20. Z. Yan, B. Wu, X. Gao, M.-W. Chen and Y.-G. Zhou, Org. Lett., 2016, 18, 692–695 CrossRef PubMed.
  21. N. Sudhapriya, C. Balachandran, S. Awale and P. T. Perumal, New J. Chem., 2017, 41, 5582–5594 RSC.
  22. M. R. Sivala, S. R. Devinenib, M. Gollac, V. Medarametlab, G. K. Pothuru and N. R. Chamarthic, J. Chem. Sci., 2016, 128, 1303–1313 CrossRef.
  23. X.-C. Li, S.-S. Gong, D.-Y. Zeng, Y.-H. You and Q. Sun, Tetrahedron Lett., 2016, 57, 1782–1785 CrossRef.
  24. S.-G. Lee, J. H. Park, J. Kang and J. K. Lee, Chem. Commun., 2001, 1698–1699 RSC.
  25. J. Tang, L. Wang, W. Wang, L. Zhang, S. Wu and D. Mao, J. Fluorine Chem., 2011, 132, 102–106 CrossRef.
  26. F. Xu, Y. Luo, M. Deng and Q. Shen, Eur. J. Org. Chem., 2003, 4728–4730 CrossRef.
  27. S. Chandrasekhar, S. J. Prakash, V. Jagadeshwar and C. Narsihmulu, Tetrahedron Lett., 2001, 42, 5561–5563 CrossRef.
  28. Z. P. Zhan and J. P. Li, Synth. Commun., 2005, 35, 2501–2504 CrossRef.
  29. N. Azizi and M. R. Saidi, Eur. J. Org. Chem., 2003, 4630–4633 CrossRef.
  30. Z. Rezaei, H. Firouzabadi, N. Iranpoor, A. Ghaderi, M. R. Jafari, A. A. Jafari and H. R. Zare, Eur. J. Med. Chem., 2009, 44, 4266–4275 CrossRef PubMed.
  31. R. G. Noronha, C. C. Romão and A. C. Fernandes, Catal. Commun., 2011, 12, 337–340 CrossRef.
  32. I. R. Cabrita, S. C. A. Sousa, P. R. Florindo and A. C. Fernandes, Tetrahedron, 2018, 74, 1817–1825 CrossRef.
  33. J. G. Pereira, S. C. A. Sousa and A. C. Fernandes, ChemistrySelect, 2017, 2, 4516–4521 CrossRef.
  34. J. A. T. Caetano and A. C. Fernandes, Green Chem., 2018, 20, 2494–2498 RSC.
  35. L. T. Mika, E. Cséfalvay and Á. Németh, Chem. Rev., 2018, 118, 505–613 CrossRef PubMed.
  36. J. M. R. Gallo, D. M. Alonso, M. A. Mellmer, J. H. Yeap, H. C. Wong and J. A. Dumesic, Top. Catal., 2013, 56, 1775–1781 CrossRef.
  37. E. R. Garrett and B. H. Dvorchik, J. Pharm. Sci., 1969, 58, 813–820 CrossRef PubMed.
  38. K. Dussan, B. Girisuta, M. Lopes, J. J. Leahy and M. H. Hayes, ChemSusChem, 2015, 8, 1411–1428 CrossRef PubMed.


Electronic supplementary information (ESI) available. See DOI: 10.1039/c8gc01343h

This journal is © The Royal Society of Chemistry 2018