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Journal of Chemistry
Volume 2013 (2013), Article ID 916960, 5 pages
http://dx.doi.org/10.1155/2013/916960
Research Article

Iodine-Mediated Neutral and Selective N-Boc Deprotection

1Department of Chemistry, Acharya Nagarjuna University, Guntur, Andhra Pradesh 522510, India
2Dr. Reddy's Institute of Life Science, University of Hyderabad Campus, Hyderabad 500046, India
3Department of Chemistry, Krishna University, Machilipatnam, Andhra Pradesh 521001, India

Received 6 May 2013; Accepted 17 June 2013

Academic Editor: Hakan Arslan

Copyright © 2013 G. Pavan Kumar et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

A simple, efficient, and alternative method has been developed for the N-Boc deprotection of structurally diverse protected amines. Selective removal of N-Boc groups was achieved with excellent yields under a solvent-free condition or in a solvent using iodine as a catalyst. The methodology involving the first use of iodine for N-Boc deprotection of protected amines represents an effective and useful alternative to the previously reported methods.

1. Introduction

Amine is one of the commonly used functionalities in synthetic organic chemistry, and its protection in the form of an N-tert-butoxycarbonyl (N-Boc) derivative has become a regular strategy in the synthesis of complex natural products, peptides, or small organic molecules [1]. The key advantages of Boc group include its ease of installation and stability towards various nucleophiles including strong basic conditions in a number of chemical transformations [24]. Traditional methods for Boc-protection involve the reaction of amines with di-tert-butyl dicarbonate (Boc)2O in the presence of 4-(N,N-dimethylamino) pyridine (DMAP) [5] or inorganic bases [6]. Several strategies have been developed for the N-Boc deprotection earlier. A variety of reagents have been employed to effect this transformation, including strong acids, Lewis acids, and neutral conditions assisted by microware. Thus, N-Boc deprotection has been carried out successfully using mild acidic conditions [7] such as trifluoroacetic acid (TFA), HCl, H2SO4, aqueous phosphoric acid [8], or Lewis acids such as BF3·OEt2, TMSI, TMSOTf, TiCl4, SnCl4, AlCl3, Sn(OTf)2, and ZnBr2 [9]. The use of montmorillonite K10 clay catalyst [10] and silica gel [11] or thermolytic conditions at high temperature [12, 13] have also shown to work. Cleavage of the Boc group can be achieved in some cases under basic conditions, where the amine is activated, such as pyrroles [1416]. Microware-assisted N-Boc deprotection under mild conditions using K3PO4·H2O in CH3OH has been reported [17]. A catalyst-free N-Boc deprotection has been reported in subcritical water under pressure [18]. Recently, several N-Boc derivatives of aromatic amines and amino acids were deprotected in boiling water [19]. While many of these methods are quite elegant and effective, a few number of them however, suffer from drawbacks such as (i) longer reaction time, (ii) high temperature, (iii) low yield of products, and (iv) the use of expensive catalysts. Moreover, preparation of some of the catalysts requires cumbersome procedures. As an inexpensive and readily available reagent, iodine has attracted considerable interest due to its less hazardous nature and efficiency in various organic transformations [20]. Herein we report our preliminary results of newly found iodine-mediated N-Boc deprotection of various protected amines under a mild and solvent-free condition.

2. Experimental

2.1. General Method for N-Boc Deprotection of  1

A mixture of N-Boc protected amine 1 (1.0 mmol) and iodine (0.08 mmol) was grinded in a mortar for the time indicated in Table 2. After completion of the reaction (indicated by TLC), the mixture was diluted with CH2Cl2 (10 mL) and washed with saturated aqueous solution of sodium thiosulphate (2 × 5 mL) and then with saturated aqueous solution of NaCl (2 × 5 mL). The organic layer was collected, dried over anhydrous Na2SO4, and filtered and concentrated under low vacuum. The residue was purified by column chromatography to afford the pure products 2a–o.

3. Results and Discussion

In our initial study tert-butyl phenylcarbamate (1a) was reacted with 8 mol% of iodine at room temperature in a range of organic solvents separately. Results of this study are summarized in Table 1. A number of solvents such as DCM, CH3CN, benzene, and toluene were examined (Table 1, entries 1–4) when the deprotected aniline (2a) was isolated in good yield.

tab1
Table 1: Effect of solvents on iodine-mediated de-N-tert-butoxycarbonylation of N-Boc-aniline (1a)a.
tab2
Table 2: Iodine-mediated deprotection of N-tert butylcarbamates (1) (Scheme 1).

While the duration of the reaction was 5–12 h in all these cases, in the absence of a solvent the reaction was completed within 30 min affording the desired product in 98% yield (Table 1, entry 5). These observations encouraged us to examine the generality and scope of this method. Accordingly, a variety of aliphatic and aromatic N-tert butylcarbamates (2) were treated with iodine under a solvent free condition when the corresponding amine (1) was isolated in good yield (Table 2). A variety of aryl (entries 1–9, Table 2), heteroaryl (entries 11–14, Table 2), and aliphatic amines (entries 10 and 15, Table 2) were deprotected following this methodology. We have also examined all these reactions in DCM, and the desired amines were isolated in good yields (Table 2). Notably, the present iodine-mediated N-Boc deprotection was found to be a slower process than the iodine-mediated N-Boc protection [21], perhaps due to the higher stability of the N-tert butylcarbamate moiety of 2 than the –OCOOtBu group of Boc2O towards elemental iodine.

A plausible mechanism for iodine catalyzed N-deprotection of 1 is presented in Scheme 2. The reaction seemed to proceed via activation of the carbonyl oxygen of 1 by iodine leading to E-1 which underwent the sequential cleavage of several bonds such as C–H, C–O and C–N bond. The interaction of molecular iodine with carbonyl oxygen has been described in the literature earlier [21, 22]. For example, nucleophilic addition of indole to a carbonyl compound was catalyzed efficiently by molecular iodine [23]. It was suggested that a halogen bond [defined as intermolecular noncovalent interaction between halogen atom and electron-donor atom such as O or N (similar to hydrogen bond)] [24] between the carbonyl oxygen and iodine molecule plays a key role in the catalytic effect of iodine observed in these reactions [25]. Nevertheless, the cleavage of C–H of the tBu group perhaps was facilitated by the iodine coordinated with the carbonyl oxygen. As a result the catalyst iodine was regenerated along with the extrusion of carbon dioxide and 2-methylpropene affording the desired amine 2.

916960.sch.001
Scheme 1: Iodine-mediated N-Boc deprotection of amines under solvent-free conditions.
916960.sch.002
Scheme 2: Proposed mechanism for iodine catalyzed N-Boc deprotection of 1.

4. Conclusions

In conclusion, we have developed a simple, efficient, and alternative method for the N-Boc deprotection of structurally diverse protected amines. The selective removal of N-Boc groups was achieved with excellent yields under a solvent free condition using iodine as a catalyst. To the best of our knowledge, this is the first example of N-Boc deprotection of protected amines catalyzed by elemental iodine. The present deprotection methodology has potential to become an effective and useful alternative to the previously reported methods and may find applications in protecting group chemistry.

Acknowledgments

The authors thank the management of Acharya Nagarjuna University and Dr. Reddy’s Institute of Life Science for continuous encouragement and support.

References

  1. G. Sartori, R. Ballini, F. Bigi, G. Bosica, R. Maggi, and P. Righi, “Protection (and deprotection) of functional groups in organic synthesis by heterogeneous catalysis,” Chemical Reviews, vol. 104, no. 1, pp. 199–250, 2004. View at Publisher · View at Google Scholar · View at Scopus
  2. E. Gross and J. Meienhofer, The Peptides, vol. 3, Academic Press, New York, NY, USA, 1981.
  3. P. J. Kocienski, Protecting Groups, vol. 185, chapter 6, Thieme-Stuttgart, 1994.
  4. G. Theodoridis, “Nitrogen protecting groups: recent developments and new applications,” Tetrahedron, vol. 56, no. 16, pp. 2339–2358, 2000. View at Publisher · View at Google Scholar · View at Scopus
  5. Y. Basel and A. Hassner, “Di-tert-butyl dicarbonate and 4-(dimethylamino)pyridine revisited. Their reactions with amines and alcohols,” Journal of Organic Chemistry, vol. 65, no. 20, pp. 6368–6380, 2000. View at Publisher · View at Google Scholar · View at Scopus
  6. S. T. Handy, J. J. Sabatini, Y. Zhang, and I. Vulfova, “Protection of poorly nucleophilic pyrroles,” Tetrahedron Letters, vol. 45, no. 26, pp. 5057–5060, 2004. View at Publisher · View at Google Scholar · View at Scopus
  7. P. G. M. Wuts and T. W. Greene, Greene’s Protective Group in Organic Synthesis, John Wily and Sons, New York, NY, USA, 4th edition, 2007.
  8. B. Li, R. Bemish, R. A. Buzon et al., “Aqueous phosphoric acid as a mild reagent for deprotection of the t-butoxycarbonyl group,” Tetrahedron Letters, vol. 44, no. 44, pp. 8113–8115, 2003. View at Publisher · View at Google Scholar · View at Scopus
  9. D. S. Bose, K. K. Kumar, and A. V. N. Reddy, “A new protocol for selective deprotection of N-tert-butoxycarbonyl protective group (t-Boc) with Sn(OTf)2,” Synthetic Communications, vol. 33, no. 3, pp. 445–450, 2003. View at Publisher · View at Google Scholar · View at Scopus
  10. N. S. Shaikh, A. S. Gajare, V. H. Deshpande, and A. V. Bedekar, “A mild procedure for the clay catalyzed selective removal of the tert- butoxycarbonyl protecting group from aromatic amines,” Tetrahedron Letters, vol. 41, no. 3, pp. 385–387, 2000. View at Publisher · View at Google Scholar · View at Scopus
  11. T. Apelqvist and D. Wensbo, “Selective removal of the N-Boc protective group using silica gel at low pressure,” Tetrahedron Letters, vol. 37, no. 9, pp. 1471–1472, 1996. View at Publisher · View at Google Scholar · View at Scopus
  12. V. H. Rawal, R. J. Jones, and M. P. Cava, “Photocyclization strategy for the synthesis of antitumor agent CC-1065: synthesis of dideoxy PDE-I and PDE-II. Synthesis of thiophene and furan analogues of dideoxy PDE-I and PDE-II,” Journal of Organic Chemistry, vol. 52, no. 1, pp. 19–28, 1987. View at Scopus
  13. K. Nadia, B. Malika, K. Nawel, B. MedYazid, R. Zine, and N.-E. Aouf, “Simple and efficient cleavage reaction of the Boc group in heterocyclic compounds,” Journal of Heterocyclic Chemistry, vol. 41, no. 1, pp. 57–60, 2004. View at Scopus
  14. I. Hasan, E. R. Marinelli, L.-C. C. Lin, F. W. Fowler, and A. B. Levy, “Synthesis and reactions of N-protected 2-lithiated pyrroles and indoles. The tert-butoxycarbonyl substituent as a protecting group,” Journal of Organic Chemistry, vol. 46, no. 1, pp. 157–164, 1981. View at Scopus
  15. S. El Kazzouli, J. Koubachi, S. Berteina-Raboin, A. Mouaddib, and G. Guillaumet, “A mild and selective method for the N-Boc deprotection by sodium carbonate,” Tetrahedron Letters, vol. 47, no. 48, pp. 8575–8577, 2006. View at Publisher · View at Google Scholar · View at Scopus
  16. N. J. Tom, W. M. Simon, H. N. Frost, and M. Ewing, “Deprotection of a primary Boc group under basic conditions,” Tetrahedron Letters, vol. 45, no. 5, pp. 905–906, 2004. View at Publisher · View at Google Scholar · View at Scopus
  17. S. R. Dandepally and A. L. Williams, “Microwave-assisted N-Boc deprotection under mild basic conditions using K3PO4·H2O in MeOH,” Tetrahedron Letters, vol. 50, no. 9, pp. 1071–1074, 2009. View at Publisher · View at Google Scholar · View at Scopus
  18. G. Wang, C. Li, J. Li, and X. S. Jia, “Catalyst-free water-mediated N-Boc deprotection,” Tetrahedron Letters, vol. 50, no. 13, pp. 1438–1440, 2009. View at Publisher · View at Google Scholar · View at Scopus
  19. J. Wang, Y.-L. Liang, and J. Qu, “Boiling water-catalyzed neutral and selective N-Boc deprotection,” Chemical Communications, no. 34, pp. 5144–5146, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. J. S. Yadav, B. V. Subba Reddy, K. Premalatha, and T. Swamy, “First example of the activation of polymethylhydrosiloxane with molecular iodine: a facile synthesis of 3,6-dihydropyran derivatives,” Tetrahedron Letters, vol. 46, no. 15, pp. 2687–2690, 2005. View at Publisher · View at Google Scholar · View at Scopus
  21. R. Varala, S. Nuvula, and S. R. Adapa, “Molecular iodine-catalyzed facile procedure for N-Boc protection of amines,” Journal of Organic Chemistry, vol. 71, no. 21, pp. 8283–8286, 2006. View at Publisher · View at Google Scholar · View at Scopus
  22. Y.-H. Wang, L. Li, and X.-S. Chen, “Theoretical studies on the iodine-catalyzed nucleophilic addition of acetone with five-membered heterocycles,” Chemical Research in Chinese Universities, vol. 24, no. 4, pp. 520–524, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. B. P. Bandgar and K. A. Shaikh, “Molecular iodine-catalyzed efficient and highly rapid synthesis of bis(indolyl)methanes under mild conditions,” Tetrahedron Letters, vol. 44, no. 9, pp. 1959–1961, 2003. View at Publisher · View at Google Scholar · View at Scopus
  24. A. C. Legon, “Prereactive complexes of dihalogens XY with Lewis bases B in the gas phase: a systematic case for the halogen analogue B···XY of the hydrogen bond B···HX,” Angewandte Chemie, vol. 38, no. 18, pp. 2686–2714, 1999. View at Publisher · View at Google Scholar
  25. G. R. Desiraju and R. L. Harlow, “Cyano-halogen interactions and their role in the crystal structures of the 4-halobenzonitriles,” Journal of the American Chemical Society, vol. 111, no. 17, pp. 6757–6764, 1989. View at Scopus