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

G. Pavan Kumar,¹ D. Rambabu,² M. V. Basaveswara Rao,³ and Manojit Pal²

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 [2–4]. 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 [14–16]. 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.

Table 1: Effect of solvents on iodine-mediated de-N-tert-butoxycarbonylation of N-Boc-aniline (1a)a.

Entry
Solvent
Time
Yieldb (%)

1
DCM
5 h
94

2
CH₃CN
6 h
92

3
Benzene
9 h
88

4
Toluene
12 h
82

5
No solvent
30 min
98

aAll the reactions were carried out using the tert-butyl phenylcarbamate (1a, 1.0 mmol) and iodine (0.08 mmol) at room temperature.

bIsolated yield.

Table 2: Iodine-mediated deprotection of N-tert butylcarbamates (1) (Scheme 1).

Entry
N-tert butylcarbamates ()
Time (min)
Producta ()
Yieldb (%)
Yieldc (%) DCM solvent

1

30

98
94

2

50

90
82

3

90

92
80

4

120

90
80

5

90

82
80

6

120

90
85

7

150

86
80

8

60

92
85

9

120

90
85

10

90

82
78

11

100

85
80

12

150

82
76

13

180

80
72

14

240

86
80

15

120

84
78

aAll the reactions were carried out using the N-tert butylcarbamate 1 (1.0 mmol) and iodine (0.08 mmol) at room temperature.

bIsolated yield.

cAll the reactions were carried out using DCM (5 mL) at room temperature for 5-6 h.

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.

Scheme 1: Iodine-mediated N-Boc deprotection of amines under solvent-free conditions.

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.

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