N-tert-Butoxycarbonylation of Structurally Diverse Amines and Sulfamides under Water-Mediated Catalyst-Free Conditions

A simple, efficient, and eco-friendly protocol for the N-Boc protection of the amine moiety in a variety of compounds with di-tert-butyl dicarbonate under water-acetone catalyst-free conditions is described. The corresponding monocarbamate is obtained in excellent yields on short reaction times. No competitive side reactions such as isocyanate urea and O-Boc were observed. This method represents a reasonable alternative to the previous reported protection procedures.


Introduction
The protection of a functional group can be essential in the chemistry of poly functionalised molecules, when a reaction has to be carried out in a part of the compounds without the rest perturbing of the molecule. The development of simple and eco-friendly methods for the protection and deprotection of functional group continues to be a significant tool in synthetic chemistry of polyfunctional molecules [1,2].
Nitrogen protection continues to attach a great deal of attention in a wide range of chemical fields, such as peptides, nucleosides, heterocyclic compounds, and other natural products. The protection of amines with tert-butyloxycarbonyl (Boc) group is a widely used reaction in organic synthesis because of its inertness toward catalytic hydrogenolysis and resistance toward hydrolysis under most basic conditions and nucleophilic reagents [3]. N-Boc deprotection is generally achieved under mild acidic conditions such as trifluroacetic acid (TFA), aqueous phosphoric acid in THF [4], or Lewis acid [5]. The deprotection can be carried out with montmorillonite K.10 clay [6], silica gel at low pressure [7], and by thermolytic cleavage although at high temperature [8,9].
The base-catalyzed reactions are often associated with the formation of isocyanate [16], urea [10], and N, Ndi-Boc derivatives [17]. Moreover, the high toxicity of DMAP and reagents derived from it limits their use [18].  [24], Cu (BF 4 ) 2 [25], sulfonic acid functionalized silica [26], and HClO 4 -SiO 2 [27]. More recently, Akbari et al. reported an efficient protocol for the N-protection of various structurally amines using protic 1, 2, 3, 3-tetra-methyguanidinium acetate as recyclable catalyst under solvent free condition at room temperature [28]. Many of these methods suffer from disadvantages such high acidity, expensive reagents, and using more excess. Excessive amounts of catalysts, high temperature and slow rate reaction. Chankeshwara and Chakraborti [29] reported the catalyst-free chemoselective N-tert-butyloxycarbonylation of amines in water. This method is not reproducible because the limited solubility of (Boc) 2 O in water under ambient conditions.
In recent years, much attention has been focused on searching greener or environmentally friendly chemical process. Water is the main solvent for life processes, and there is growing interest in using it as green solvent for organic transformations [30,31]. However, reports about using water as a catalyst to promote organic reactions are very limited. Compared to conventional solvents water is preferred for organic reaction because it displays unparalleled and unique properties. Moreover, it is cheap, nontoxic, nonexplosive, and environmentally acceptable [32,33]. Thus, the use of water instead of organic solvents has gained much importance in the development of sustainable protection in generally chemistry.
In this paper, we report efficient and eco-friendly protocol for chemoselective N-tert-butyloxycarbonylation of various structurally amines in water-related system under ambient conditions in the absence of any acid/base-catalyst.

Results and Discussion
In our quest of a "greener" approach toward N-Boc protection, we have carried out a series of experiments using commercially available di-tert-butyldicarbonate (tert-BuOCO) 2 O and various structurally amines and water as solvent (Scheme 1). The N-tert-butyloxycarbonylation of various amines (Table 1) was carried out in distilled water with a minimum of aceton at room temperature and atmospheric pressure in the absence of any catalyst (Scheme 1).
The reactions were completed after 8-12 min, affording Boc protected amines in good and excellent yields (Table 1) and short time. In each case, only the mono N-Boc protected product was found. No isocyanate or urea formation was detected (by NMR of crude products).
The critical amount of water required was found to be 1 mL/mmol of amine and the minimum of the aceton for the solubility of (Boc) 2 O. The products were isolated by filtration (for solid products) or extraction with CH 2 Cl 2 (for liquid products). ISRN Organic Chemistry 3 R R

9a-13a
OMe The chemoselectivity was further demonstrated in the case of p-aminophenol (entry 5) that did not form oxazolidinone.
To explore the scope and limitations of this reaction and view of the importance of peptide synthesis, we investigated the Boc-protection of various aminoesters derivatives of (Leu, Ala, Val, Leu, and Phe) ( Table 2, entries 9-13).
All N-Boc-protected aminoesters were prepared from the corresponding starting from aminoacids after esterification and protection by reacting with (Boc) 2 O in water at room temperature (Scheme 2).
As can be seen ( Table 2, entries 9-13), the N-Boc protection process was quite satisfactory because it could be quantitatively converted to its N-Boc esters of α-amino acids.
It was quite interesting to observe the N-Boc protection of many of the substrates gave optically pure N-Boc derivatives (as determined by optical rotation and comparison with literature values).
As can be seen from results in Table 2, the isolated yield of 9a-13a were in the range of 92-96%, the reaction could be completed in 5 min and 12 min.
Encouraged by these experimental results, we extended our studies to series carboxylsulfamides aminoester derivatives (Scheme 3, Table 3).
The N-Boc protection reaction was studied using compounds 14-18 as substrates in the same conditions. 1.0 mmol was treated with (Boc) 2 O 260 mg, 1 mmol in water : acetone at room temperature (Table 3, entries 14-18). The reaction was monitored by TLC. In most of cases, the desired product was obtained in good at excellent yields (Scheme 3).
The reaction preserves stereochemical integrity of amino esters derivatives. The reactions were rapid with most of the sulfamides studied (5-10 min) and were compatible with diverse sulfamides.
The propriety of this method can be formative of the application in the organic synthesis and particularly in peptide synthesis.
To explore the scope and limitations of this reaction, we extended our study the N-protection of cyclosulfamides (Scheme 4).
The synthesis of the cyclosulfamides (entries 19-23) was achieved starting from CSI, and amino acids (Gly, Ala, Val, Leu, and Phe) according a general procedure previously described [34]. The derivatization of amino acids allowed the introduction of an alkyl group on C-4 well-defined configuration.
The cyclosulfamides (Table 4, entries 19-23) were tested under the same conditions of present protocol. The reaction is monitored by TLC, which indicates complete disappearance of (19-23) within 8 min at room temperature and atmospheric pressure, to afford the corresponding Nprotected cyclosulfamides (19a-23a) with excellent yields.
To explore the mechanism of these processes, we assume that hydrogen bond formation between water and the carbonyl oxygen atom of (Boc) 2 O causes electrophilic activation of the carbonyl group which make more susceptible to nucleophilic attack. Intramolecular nucleophilic attack by the nitrogen atom on the carbonyl carbon activated followed by release of CO 2 , t-BuOH, H 2 O and forms the carbamate (Scheme 5).
The structures of all the compounds were unambiguously confirmed by usual spectroscopic methods. For the final derivatives, the different NMR spectra showed a signal of NH proton and appearance of signal corresponding to the tert-butyl protons. These compounds exhibited characteristic absorption in the IR spectrum with the absorption at 1702-1712 cm −1 (C=O).

Conclusions
In summary, we have developed a novel and efficient route for water-mediated N-tert-butoxycarbonylation of amines at room temperature. The absence of acid/base and the use of water makes present procedure environmentally friendly. We are exploring the protection of various diverse amines with other protecting groups applications and will report the finding in due course.

Experimental Section
All commercial chemicals and solvents were without further purification.
The synthesis of the compounds, starting from (CSI) chlorosulfonyl isocyanate tert-butyl alcohol and methyl esters of amino acids (glycine, L-alanine, L-leucine, and Lphenyalanine) has been previously reported [34].
N-Boc Protection: General Procedure. In a 50 mL round flask with 9.5 mL of distilled water and 0.5 mL acetone, 1 mmol of amine was added, the mixture was stirred at room temperature for the few minutes.
Dichloromethane was added (5 mL), and the mixture was stirred. Progress of the reaction is monitored by TLC, which indicates complete disappearance of precursors amines. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuum. The residue was purified by column chromatography on silica gel with (CH 2 Cl 2 /MeOH, 9 : 1) to afford the N-Boc amines derivatives in high yields.
The synthesis of the compounds 14-23 has been previously reported for our research group [35,36].