Rapid and Efficient N-tert-butoxy carbonylation of Amines Catalyzed by Sulfated Tin Oxide Under Solvent-free Condition

A straightforward, rapid, and efficient protocol for the N-tert-butoxy carbonyl (N-Boc) protection of amines (aromatic, aliphatic) using sulfated tin oxide catalyst is illustrated. N-Boc protection of various amines was carried out with (Boc)2O using sulfated tin oxide as a catalyst at room temperature under solvent-free conditions. Rapid reaction times, ease of handling, cleaner reactions, easy work-up, reusable catalyst, and excellent isolated yields are the striking features of this methodology which can be considered to be one of the better methods for the protection of amines and alcohols.


Introduction
Protection of the amino functionality of amino acids is one of the most important issues in peptide chemistry and is mandatory to prevent polymerization of the amino acid once it is activated. Boc-protection has become a fundamental tool of the Merrifield strategy for solid-phase peptide synthesis (SPPS). Among different methods; the N-tert-butoxycarbonyl (N-Boc) protection has been widely used for the amino acids during peptide synthesis due to their resistance towards racemisation [1][2][3]. In synthetic organic chemistry, protection and deprotection of functional groups constitute a crucial strategy in the protection of primary and secondary amines [4][5][6]. Owing to the high stability of the corresponding N-tertbutylcarbamates, this group can be exposed to a number of chemical transformations safely.
Moreover, due to its labile nature towards mild acidic conditions it can be converted back to the parent amine easily. These N-tertbutoxycarbonyl protected amines are widely used in the synthesis of polyamines and heteromacrocycles and in the construction of biological active compounds [7][8][9][10].
Among the different available reagents used for N-Boc protection such as BocONH2, BocN3, BocON=N(CN)Ph and 1-(tertbutoxycarbonyl)benzotriazole, the di-tert-butoxy pyrocarbonate is the most popular reagent because of its commercial availability, low cost, stability, and efficiency. However, there are quite a lot of problems behind the classical N-Boc protection technique. To overcome these problems, variety of reagents and methodologies were developed over the years. For the preparation of N-tert-butyl carbamates using ditert-butyl dicarbonate (Boc)2O have been carried out either in the presence of a base (DMAP, aq NaOH, NaHMDS) or more recently acid catalysts and other reagents [11][12][13][14][15][16][17][18][19][20][21][22]. These methods mentioned above are valuable, but frequently suffer from the drawbacks such as long reaction times, lack of reactivity, formation of sideproducts, the use of corrosive and moisturesensitive reagents, and the tedious work-up procedures.
In order to avoid some of the problems associated with these procedures and also in continuation of our ongoing work on solid acid (supported or not) catalysts, towards the ecofriendly organic synthesis [23][24][25][26][27][28] herein, we introduce promoted tin (stannum) as an efficient solid acid catalyst for the rapid synthesis of Ntert-butoxy carbonylated amines under solventfree conditions. A few supported versions or versions based on heterogeneous catalysts have recently been described, but no tin (stannum)based catalyzed version has so far been reported [29][30][31][32][33].

Results and Discussion
Owing to the ever-mounting environmental concern in the field of chemistry, it is desirable to use environmental friendly green methods in organic synthesis. Recently, SO4 2− /SnO2 has emerged as an attractive alternative catalyst in terms of acidic strength and environmentally benign character for various reactions. We carried out our initial experiment using aniline as a model substrate. At room temperature, when 50 mg of the SO4 2− /SnO2 catalyst was added to the mixture of one mmol of aniline and one mmol of Boc2O under solvent-free conditions, there was an evolution of heat and quick bubbling. To our delight, this model reaction finished within one minute and the corresponding mono N-Boc derivative was afforded in 99% yield (isolated). It may be noted here that N-Boc group is not affected by the acidity of the solid acid catalyst.
To optimize the reaction conditions, solvent and the amount of catalyst (SO4 2− /SnO2), we selected the common reaction that is the reaction between aniline and di-tert-butyl dicarbonate as a model reaction. The results are summarized in Table 1. Lower catalytic activity is observed for various organic solvents such as CH2Cl2, CH3CN, toluene, benzene, MeOH, and H2O under room temperature and 50 mg SO4 2− /SnO2 catalyst, which probably due to interference of the solvent with active sites of the catalyst ( Table  1, entry 1-6). On the contrary, reaction worked well under solvent-free condition ( Table 1, Entry  7). Screening experiments in various solvents established that reaction progresses very well under solvent-free conditions compared to solvent system (Table 1).
A comparative study of our procedure with the reported literature for the synthesis of N-tertbutoxycarbonyl protected amines has been presented in Table 2. As shown in Table 2, our catalyst (SO4 2− /SnO2) demonstrated rapid reaction time (1 min) and high isolated yield (99%) at mild and solvent-free conditions when compared to other catalysts ( Table 2, entry 7). Interestingly, N-tert-butoxy carbonylation of the aniline revealed very low yield of the product with trace amounts of side products in the absence of catalyst for 2 days of reaction time ( 0.05 --01 ∼100 a isolated yields of pure desired products. Solid acid catalyst (SO4 2− /SnO2) offers ease of handling and purification, through simple filtration. They also allow catalyst recovery and recycling, which is an interesting eco-friendly aspect. In order to examine this possibility, after the reaction, the SO4 2− /SnO2 catalyst was conveniently removed by simple filtration from the reaction mixture. The wet catalyst was reused for the reaction and there was no big change in the catalytic activity in the next 5 cycles. With these environmental-friendly conditions in hand, we then explored the scope of this new promoted tin-based solid acid catalyzed N-tert-butoxycarbonylation of amines. In the mean time, we also investigated the role of aromatic and aliphatic amines with substituents on this N-tert-butoxycarbonylation reaction (Scheme 1 and Table 2).
Different types of amines namely, aromatic, aliphatic, and benzyl amines were used to evaluate the possibility in N-Boc protection. Reaction of aromatic amines with di-tert-butyl dicarbonate (Table 3, entries 1, 2, 5, 7, 9−12) took place very fast within 6 minutes. Even the N-Boc protection of aliphatic amines also achieved within 5 minutes of reaction time ( Table  3, entries 3 and 4). Our catalyst SO4 2− /SnO2 showed an impressive performance towards Ntert-butoxy carbonylation of amines to achieve rapid reaction times and superior yields without any side reaction, such as bis carbonylation or the formation of isocynate or urea.

Preparation of Catalyst
About 25 g of SnCl4 5H2O (Sigma Aldrich) was dissolved in doubly distilled water. To this clear solution, dilute aqueous ammonia was added drop-wise from a burette with vigorous stirring until the pH of the solution reached 8. The obtained precipitate was washed thoroughly with distilled water until free from chloride ions and dried at 393 K for 16 h. To prepare sulfated SnO2 catalyst, a portion of the obtained tin (IV) hydroxide sample was ground to fine powder and immersed in 15 cm 3 /g of 0.5 M H2SO4 solution for 30 min. Excess water was evaporated on a water-bath and the resulting sample was ovendried at 393 K for 12 h and calcined at 773 K for 3 h in air atmosphere and stored in a vacuum desiccator.

General Methods
Chemicals are commercial products and were used without further purification. The products were characterized using FT-IR spectra and were recorded on a Perkin-Elmer Fourier transformation (FT)-IR 240-C spectrophotometer using KBr discs. 1 H−NMR spectra were recorded on a Gemini-200 spectrometer in CDCl3 using tetramethylsilane (TMS) as the internal standard. Mass spectra were recorded on a Finnigan MAT 1020 mass spectrometer operating at 70 eV.

General procedure for synthesis of Boc protection of amines
A mixture of amine (1 mmol), (Boc2O) (1 mmol), and SO4 2− /SnO2 solid acid catalyst (50 mg) was stirred at room temperature for appropriate time under N2 atmosphere. After completion of the reaction, as indicated by TLC, the reaction mixture was filtered and washed with CH2Cl2 (10 ml) and the catalyst was separated by filtration. The combined organic layers were dried over anhydrous Na2SO4. The filtrate was collected and concentrated. The residue was purified by column chromatography to obtain the pure product. The same general procedure was applied for other reactions. On each occasion, the product was identified by comparing the spectroscopic data (IR, NMR, and MS) with those reported in the literature.

Conclusions
In conclusion, we have developed a novel protocol for the N-tert-butoxycarbonylation of amines with rapid reaction times under solventfree conditions using highly efficient and reusable SO4 2− /SnO2 solid acid catalyst. With the intension of increasing tight legislation on the release of waste and use of toxic substances as a measure to control environmental pollution, the use of a stoichiometric amount of reagents and the solvent-free conditions employed in the present method is an attempt to develop more efficient, environmentally friendly, and suitable for industrial implementations.