Functional group protection and deprotection methods are important in the synthesis of the organic compounds. The N-amine protecting groups have been used extensively across a wide range of chemical fields,such as peptide,nucleotide,polymer,and ligand preparations. Several methods and reagents have been reported for the protection of amine and amino groups ^{[1, 2, 3, 4, 5]}. Among them,Ntert- butoxycarbonylation has received the greatest attention because of the stability of the N-Boc group against nucleophilic attack or alkali media and catalytic hydrogenation ^{[6, 7]}.

Some catalytic systems such as indium (III) halides ^[6],DMAP ^[8],NaHMDS ^[9],Zn(ClO₄)₂·6H₂O ^[10],ZrCl₄ ^[11],LiClO₄ ^[12], yttria-zirconia ^[13],copper tetrafluoroborate ^[14],ionic liquid [(HMIm) BF₄] ^[15],1-alkyl-3-methylimidazolium cation ^[16], HClO₄-SiO₂ ^[17],sulfamic acid ^[18],sulfonic acid-functionalized silica ^[19],b-cyclodextrine ^[20],thiourea ^[21],iodine CsF ^[22], H₃PW₁₂O₄₀ ^[23],montmorillonite K10 and KSF ^[24],indion 190 resin ^[25],ionic liquid [TMG][Ac] ^[26] and 1,3-disulfonic acid imidazolium hydrogen sulfate ^[27],and NH₂OH ^[28] have been used for N-tert-butoxycarbonylation of amines. However,these proposed methods have limits such as the use of toxic,hazardous and expensive reagents,long reaction times,low yields,adverse reactions that produce a mixture of products,and multiple stages.

Ionic liquids are extensively being used as green solvents and efficient catalysts for the preparation of organic compounds because of their unique properties such as excellent chemical and thermal stability,good solvating capability,wide liquid range, variable polarity,low vapor pressure,and recyclability. As mentioned above,ionic liquids have already been used for this important reaction and satisfactory results have been achieved. Given the importance of these compounds in order to meet the demands of green chemistry,development of synthetic methods in ionic liquids as solvents or as catalysts has been of interest to researchers. In this regard,we introduce [Py][OTf] as an acidic ionic liquid in the N-protection of amines. The simple preparation and the ability to be recycled up to seven runs are salient features of this catalytic system. 2. Experimental

General procedure for the N-Boc protection of amines: To a magnetically stirred mixture of amine (1 mmol) and (Boc)₂O (1 mmol) a catalytic amount of ionic liquid (0.2 mmol) was added under solvent-free conditions at room temperature for the specified period of time. The progress of the reaction was monitored by TLC and GC-MS. The mixture extraction was carried out using ethyl acetate (2 × 5 mL). The organic layer was washed with water (2 × 10 mL) and dried over anhydrous Na₂SO₄. The solvent was evaporated under vacuum to yield highly pure N-Boc derivatives. In some cases,the purification was done by column chromatography using silica gel (60-120) by hexane-ethyl acetate as eluent to get a pure product. 3. Results and discussion

In continuing our interest on ionic liquid as a catalyst in the synthesis of organic compounds ^[29],here we report the selective tert-butoxycarbonylation of amines using (Boc)₂O catalyzed by pyridinium 2,2,2-trifluoroacetate [Py][OTf] ionic liquid as a novel catalyst at room temperature with high yields and short reaction times (Scheme 1).

Scheme 1

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Scheme 1.N-Boc protection of amines.

To find the optimal conditions,the reaction between aniline and (Boc)₂O was chosen as a model reaction. Initially,the reaction was performed under the solvent and catalyst free condition,and as can be seen in Table 1,after 180 min of reaction time,the product was obtained in 80% yield (Table 1,entry 1). By using 0.2 mmol of [Py][OTf] ionic liquid as catalyst,97% yield of product was obtained in the period of 25 min (Table 1,entry 2). The effect of different solvents on the reaction efficiency was tested but the reaction in the solvent-free conditions had the best performance (Table 1, entries 3-7). Finally,the amount of catalyst was studied and by reducing it,the reaction yield was significantly reduced. (Table 1, entries 8-9). Interestingly,by increasing the amount of catalyst to 0.3 mmol,the yield for unknown reasons was decreased to 90% after 25 min of reaction time (Table 1,entry 10).

Table 1

Table 1 The optimal reaction conditions for the model reactiona.a

Table 1 The optimal reaction conditions for the model reactiona.a

The following conditions were used for the preparation of various amine carbamates: amine (1 mmol),(Boc)₂O (1 mmol),[Py][OTf] (0.2 mmol),room temperature. Various derivatives of aniline and benzyl amine were taken under the reaction conditions and the products were obtained with good yields (Table 2). In general,benzyl amine derivatives reacted more quickly than aniline derivatives due to their high nucleophilicity. As expected, electron donating groups on aryl groups give rise to higher yields than electron withdrawing groups.

Table 2

Table 2 Preparation of amine carbamates 3a-p in the presence of [Py][OTf] ionic liquid as catalyst.

Table 2 Preparation of amine carbamates 3a-p in the presence of [Py][OTf] ionic liquid as catalyst.

To see the advantages of [Py][OTf] as a catalyst in this reaction, our obtained results and employed reaction conditions for preparation of tert-butyl phenyl carbamate (3a) were compared with previously reported data in Table 3. The results show the proposed method with [Py][OTf],as catalyst is quite better than the former methods in yields and reaction times.

Table 3

Table 3 A comparison of the efficiency of [Py][OTf] with several reported procedures in the preparation of tert-butyl phenyl carbamate 3a.

Table 3 A comparison of the efficiency of [Py][OTf] with several reported procedures in the preparation of tert-butyl phenyl carbamate 3a.

To examine the reusability of [Py][OTf] in the model reaction after completion the reaction mixture was extracted by ethyl acetate and the catalyst was separated,washed with ethyl acetate and EtOH,air-dried,and used directly for the next reaction without further purification. The [Py][OTf] ionic liquid could be recovered and reused seven times without any significant loss of the catalytic activity (Table 4).

Table 4

Table 4 Reusability of the [Py][OTf] in the synthesis of compound 3a

Table 4 Reusability of the [Py][OTf] in the synthesis of compound 3a.

A suggested mechanism for the formation of amine carbamates catalyzed by [Py][OTf] is shown in the Scheme 2. First,the carbonyl group of (Boc)₂O is activated by hydrogen bond formation with the acidic hydrogen of [Py][OTf]. Then,the nitrogen of the amine attacks the activated carbonyl group. Amine carbamate is prepared by evolving one molecule of CO₂ and tert-butyl alcohol. 4. Conclusion

In conclusion,we have developed a fast,simple,and efficient procedure for N-protection of amines based on [Py][OTF]- catalyzed reaction of amines and (Boc)2O,under solvent-free conditions at room temperature. The short reaction times,easy workup,clean reaction profiles,and high product yields make our methodology a valid contribution to the existing processes in amines protections.

Scheme 2

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Scheme 2.Suggested mechanism for the formation of amine carbamates.

The authors thank the Research Committee of Persian Gulf University and Guilan University for financial support of this work.