General solvent-free highly selective N-tert-butyloxycarbonylation strategy using protic ionic liquid as an efficient catalyst

Abstract

A simple, rapid and solvent-free protocol is described for the chemo-selective transformation of amines to tert-butyloxycarbonyl protected derivatives (NHBoc) using Boc₂O and imidazolium trifluoroacetate protic ionic liquid (5–20 mol%). Unwanted side products such as isocyanate, urea or N,N-di-Boc were not detected. The scope of the protection strategy was successfully explored for substrate alcohols, phenols and thiol at elevated temperatures. Optically pure amino acids, amino acid esters and amino alcohols were efficiently converted to the corresponding N-Boc protected derivatives in excellent yields without racemization at the chiral center. The distinct advantages of this method are: operational simplicity, cleaner reaction, high selectivity, excellent yield, rapid reaction convergence, easy preparation and recyclability of the catalyst.

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The protection and deprotection of a functional group can be essential in the chemistry of multi-functionalized molecules in target oriented synthesis.¹ The choice of a suitable protecting group is often crucial in the context of simplicity of the procedure, highest yield of the desired product, easy workup and separation. The protection of amines plays an important role in organic synthesis especially in peptide chemistry. Among the wide variety of available amine protecting group, the tert-butyloxycarbonyl (Boc) protecting group has demonstrated to be most useful because it has all the fundamental properties for an ideal protecting group such as easy availability of the reagents for its installation, inertness in various reaction conditions and simple deprotection.^1–3 There are various conventional base mediated strategies are available for the N-Boc protection of amines in the literature.⁴ However, the base catalyzed reactions often lead to formation of undesirable side products such as isocyanate, urea and N,N-di-Boc derivatives.⁵ To circumvent the above mentioned drawbacks, several Lewis acid or solid acid catalysts⁶ are available to effect the conversion of amines to the corresponding N-Boc protected compounds. In spite of their potentiality they are also plagued by a number of other drawbacks such as difficulties associated with the preparation such as use of solid acid catalysts (long reaction time, tedious work-up), moisture sensitivity, many of them is corrosive and moreover some of them can be deactivated by the amines. Therefore, new, mild and eco-friendly protocols for N-Boc protection are still in demand. In recent times, ionic liquids have received considerable interest as alternative to the traditional environmentally harmful volatile organic solvent. Ionic liquids can be used simultaneously as eco-friendly solvents, catalysts and reagents in the context of green synthesis⁷ because of their unique properties, such as low volatility, non-flammability, high thermal stability, negligible vapour pressure and ability to dissolve a wide range of compounds. Moreover, imidazolium based ionic liquids particularly protic ionic liquids has been selected as novel reaction media for promoting various organic transformations due to their water miscibility and other useful characteristics of solid acids and mineral liquid acids.⁷ Therefore, replacement of conventional harmful acid catalyst to protic ionic liquid promoted solvent free reactions not only simplifies organic synthesis but also improve process conditions for large scale synthesis. Recently S. Sunitha et al.⁸ has reported 1-methyl imidazolium tetrafluoroborate [(HMIm)BF₄] as a catalyst for N-tert-butyloxycarbonylation of amines. The catalyst [(HMIm)BF₄] was prepared by mixing of 1-methyl imidazole with 40–50% aqueous HBF₄ (pure HBF₄ never prepared) at room temperature.⁹ Removal of excess HBF₄ and water from the ionic liquid is laborious, time and energy consuming process and has limited substrate scope. During the preparation of our manuscript, N-tert-butyloxycarbonylation of amines particularly aromatic amines and some benzylic amines were reported¹⁰ using pyridine based protic ionic liquid. However pyridine based ionic liquid is more toxic and volatile nature in contrast to its imidazole analogues and it could not find diverse application. To the best of our knowledge N-tert-butyloxycarbonyl protection of amino acids and other chiral compounds using imidazolium trifluoroacetate protic ionic liquid is unexplored which is very much simple to prepare.¹¹ It can be achieved just by mixing of equimolar amount of any N-1 substituted imidazole with pure trifluoroacetic acid without the use of any additional solvents. Any trace of TFA (bp 72 °C) can be removed during vacuum drying. The ease preparation, handling and high water solubility of imidazolium trifluoroacetate based ionic liquids prompted us¹² to investigate their uses as solvents and/or catalyst in the tert-butyloxycarbonylation. Herein, we wish to disclose a highly efficient and chemo-selective protocol for the tert-butyloxycarbonylation of amines, amino acids, amino acid esters, amino alcohols, alcohols, phenols and thiols using catalytic amount of protic ionic liquid under solvent-free reaction conditions.

During our initial investigation, aniline was treated with Boc₂O in presence of different imidazolium based protic ionic liquid in various reaction conditions. The results were summarized in Table 1. Reaction of aniline (1a) with Boc₂O was completed in presence of 1-methyl imidazolium-trifluoroacetate (20 mol%) in dichloromethane (DCM) at room temperature in 20 min and the desired product 4a was obtained in excellent yield (92%, Table 1, entry 1). Yield was improved to 94–95% on use of 1-butyl imidazolium or 1-butyl-2-methyl imidazolium trifluoroacetate as a promoter (entries 2 and 3). Change of solvent such as DCM to acetonitrile (MeCN) did not improve the yield (entry 4). Gratifyingly, the reaction time (5 min) and yield (99%) were drastically improved under solvent-free reaction conditions using 20 mol% of 1-butyl-2-methyl imidazolium trifluoro-acetate as a catalyst (entry 5). However, the reaction rate was slowed down (10 min) on decreasing the catalyst loading (5 mol%, entry 6). No reaction took place in DCM (3 h) without protic PIL (entry 7). The role of PIL was ascertained as follows: equimolar mixture of aniline and Boc₂O was stirred vigorously at room temperature for 30 min but commencement of effervescence was not observed. Upon addition of the protic ionic liquid (5 mol%) to the reaction mixture there was immediate exothermic evolution of gas with concomitant formation of the corresponding N-Boc derivative in 98% yield which was confirmed by monitoring in TLC, ¹H NMR and GC-MS analyses. Incomplete conversion (∼50%) was observed in absence of the catalyst that afforded 4a in 40% yield after 48 h (entry 8).

Table 1 Optimization of PIL catalyzed Boc protection reaction of amine functionality

Entry	PIL catalyst (mol%)	Solvent	Time (min)	Yield (%)
1	1-Methyl imidazolium-trifluoroacetate (20)	DCM	20	92
2	1-Butyl imidazolium-trifluoroacetate (20)	DCM	20	94
3	1-Butyl-2-methyl imidazolium-trifluoroacetate (20)	DCM	20	95
4	1-Butyl-2-methyl imidazolium-trifluoroacetate (20)	MeCN	20	94
5	1-Butyl-2-methyl imidazolium-trifluoroacetate (20)	None	5	99
6	1-Butyl-2-methyl imidazolium-trifluoroacetate (5)	None	10	98
7	None	DCM	3 h	NR
8	None	None	48 h	40
9	1-Butyl-2-methyl imidazolium-trifluoroacetate (5)	None	5	99, 96, 94, 93, 89

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With this optimized process in hand (Table 1, entry 6), the efficacy of our protocol was evaluated using various amines (1) with Boc₂O under the catalysis of 1-butyl-2-methyl imidazolium-trifluoroacetate (5 mol%) under the solvent-free reaction conditions to furnish corresponding N-Boc protected products (4). The scope of the benign approach is illustrated in Table 2, Table 3 and Table 4. With aryl amines the reaction rate depends on the nature of substitution as well as their relative positions in the aromatic rings. p-Toluidine reacted in a first reaction rate (20 min, Table 2, entry 1) at room temperature but o-toluidine underwent slowly (150 min) at room temperature to afford (85%, entry 2) N-Boc protected compound where as it became faster (45 min) at 70 °C to obtain much improved yield (98%, entry 3). This might be due to the steric hindrance of the o-substituent present in the aromatic ring which prevented easy attack to the one of the carbonyl of Boc₂O. Other aromatic amines such as, 1-amino naphthalene, 1,2-diamino benzene, 2-amino pyridine, imidazole and benzimidazole (1d–h) all are converted to the corresponding N-Boc derivatives (4d–h) in excellent yield (98–99%, entries 5–8). In the case of 1,2-diamino benzene (1e), it was very difficult to control the reaction for mono-N-tert-butyloxycarbonylation. However, both the amino groups can be efficiently protected with 2.2 moles of Boc₂O (entry 5). The reaction is somewhat sluggish at room temperature for aromatic amines bearing electron withdrawing group such as 4-nitro aniline (1i) and 4-amino benzoic acid (1j) but at 70 °C the amines reacted with Boc₂O to furnish corresponding N-Boc product with good yield (72–80%, entries 9 and 10). This protocol was also equally efficient for aliphatic primary, secondary or cyclic amines which afforded corresponding Boc protected derivatives (entries 11–15) at room temperature in excellent yield (89–99%). In our experiments we observed that this protection approach is very much selective for primary amines. For instance, in our experiment to protect an equivalent mixture of aniline (primary amine) and secondary amines diphenyl amine we found only the Boc protected aniline derivative even at elevated temperature. However, on use of N-benzyl aniline only a trace of Boc-protected N-benzyl aniline was produce at higher temperature (70 °C). Both steric and electronic repulsion played important role for the inertness of these amines towards the reagent.

Table 2 Protic ionic liquid catalysed N-tert-butyloxycarbonyl (Boc) protection of amines^a

Entry	Substrate (1)	Product (4)	Temp. (°C)	Time (min)	Yield^b^,^c (%)
a 1 mmol substrate was used in each entry.b Isolated yield.c All the products were characterized by IR, ^1H & ^13C NMR data.d 2.2 equivalent Boc2O was used.
1			rt	20	98
2			rt	150	86
3			70	45	98
4			rt	30	78
5			rt	30	98^d
6			rt	60	98
7			rt	10	99
8			rt	45	98
9			70	60	80
10			70	90	72
11			rt	10	99
12			rt	20	98
13			rt	60	89
14			rt	30	95
15			rt	15	98

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Table 3 Chemoselective Boc protection of phenols and amino alcohols

Entry	Substrate (2)	Product (5)	Temperature (°C)	Time (min)	Yield (%)
a 1.1 eq. Boc2O was used.b Use of excess Boc2O did not produced any other product.c 2.2 eq. of Boc2O was used.
1			70	25	94
2			70	45	91
3			70	45	98
4			70	45	50
5			70	60	60^a
6			rt	210	90^a
7			rt	240	92^a
8			rt	5	99^a^,^b
9			70	15	98^c

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Table 4 tert-Butyloxycarbonyl protection of functionalized chiral amine

Entry	Substrate (3)	Product (6)	Temp. (°C)	Time (min)	Yield^a (%)
a Isolated yield.b Same yield was obtained when reaction was carried out in 100 mmol (11.7 g) scale.c Two drops of water was added.d Reaction was very slow at room temperature.
1			rt	20	97
2			70	15	99^b
3			70	45	81^c
4			70	45	86^c
5			70	75	86^c
6			70	60	80^c
7			rt	60	89
8			rt	45	98
9			70	30	87^d
10			rt	5	98
11			rt	5	70
12			rt	180	89

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After successful development of N-Boc protection of various aromatic, hetero-aromatic as well as aliphatic amines by catalysis of the imidazolium trifluoroacetate based protic ionic liquid we paid our attention to the protection of other functionalities such as alcohols, phenols and thiol compounds (2). Phenols, alcohols or thiols do not reacted with Boc₂O at room temperature. However, at 70 °C these compounds underwent smoothly to the desired O-Boc or S-Boc derivatives (5a–d, Table 3, entries 1–4) in good to excellent yield (78–98%). Next, we examined the chemo-selectivity of the present methodology. 4-Hydroxy benzyl alcohol (2e) was treated with 1.1 moles of Boc₂O in presence of 5 mol% of PIL. After 1 h, phenolic –OH protected compound (5e) (entry 5) was isolated in 60% yield with the formation of traces of di-Boc derivative thereby indicating that the reaction is very much chemo-selective for phenolic OH over alcohol. We were also very much pleased to observe that the reaction was highly chemo-selective at room temperature since 3 or 4 amino phenol (entries 6 and 7) and 3-amino 1-propanol (entry 8) afforded only the corresponding N-Boc protected derivatives (5f–h) as the sole product. Interestingly, on carrying out the reaction at 70 °C using 2.2 equivalent of Boc₂O, both the amino and alcohol groups of 3-amino propanol were reacted and furnished N-Boc and O-Boc protected product 5i in 98% yield (entry 9) in 15 min without generation of N,N-di-Boc or other side products.

Enormous importance of Boc protected amino group (6, Table 4) in peptide and ψ (pseudo)-peptide¹³ chemistry led us to pursue protecting amine functionality of chiral amino acids, amino acid esters and amino alcohols because the protected precursors are frequently used during synthesis of peptides. L-Leucinol (3a) was treated with Boc₂O (1.1 eq.) and 1-butyl-2-methyl imidazolium trifluoroacetate (5 mol%) catalyst which selectively afforded corresponding N-Boc protected amino alcohol in 97% yield after 20 min (Table 4, entry 1).

Free amino acids did not react with Boc₂O at room temperature, but reacted efficiently at 70 °C in presence of 20 mol% of protic ionic liquid and a little water (two drops) to afford the corresponding N-Boc amino acids in very good to excellent yield (80–99%, entries 2–6). Herein, role of water is to generate non-protonated amine functionality which is essential for initiation of N-Boc protection. In case of secondary amino acid proline, the protection reaction worked well even in 100 mmol scale (yield: 99%) in a very short period of time (entry 2). The amino acids esters were also efficiently converted to their corresponding N-Boc products without effecting ester functionality (entries 7–9). Unfortunately, Boc protection of amino acids those contains side chain functional group such as serine, histidine and tyrosine under the same reaction conditions were unsuccessful due to completely insoluble nature of the precursors under the reaction conditions. However, use of methyl ester of these amino acids greatly improves their solubility and the reaction underwent smoothly with Boc₂O at room temperature under the catalysis of 2-methyl-1-butyl imidazolium trifluoroacetate to afford the corresponding Boc protected amino acid esters (6j–l) in good to excellent yield and selectivity (entries 10–12). As expected phenolic –OH group was not participated Boc protection reaction at room temperature. In the case of methyl ester of histidine (3k) both α-amino group and NH of imidazole ring undergoes tert-butyloxycarbonylation reaction. Racemization of the chiral centers was not observed in all cases (Table 4) which was determined by optical rotation measurement of the products with comparison of the available literature data.¹⁴

Since the practical utility of any catalytic process depend on reusability of the catalyst, therefore recyclability of protic ionic liquid was investigated and assessed by conducting N-tert-butyloxycarbonylation of aniline with 20 mol% of 1-butyl-2-methyl imidazolium trifluoroacetate. We observed that the catalytic activity of protic ionic liquid was retained over five successive cycles within yield of 99–89% (Table 1, entry 8). The proposed catalytic cycle by the powerful PIL (I) is depicted in Scheme 1. Mechanism of the transformation is expected to be initiated through activation of carbonyl of Boc₂O by protic ionic liquid which finds extra stabilization from neighboring CF₃CO₂⁻ (II). This electrophilic activation greatly facilitates nucleophilic attack by the –XH functionality (III) of the substrates (1–3) to release Boc protected desired compounds (4–6). Subsequent removal (IV) of carbon dioxide and tert-butanol leads to generation of the catalyst for the next cycle (Scheme 1).

Scheme 1 Possible catalytic cycle for N-tert-butyloxycarbonylation.

General procedure for N-tert-butyloxycarbonylation of amines

A mixture of Boc₂O (5.0 mmol), protic ionic liquid (5 mol%) and an amine (5.0 mmol) was stirred at room temperature or 70 °C for the time indicated in the Tables. After completion of reaction as revealed by TLC, the mixture was diluted with water (5 ml) and extracted with diethyl ether or ethyl acetate (3 × 10 ml). The aqueous layer was recycled. The combined organic layer was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude products were essentially pure but for analytical data, the samples were passed through short pad silica-gel (60–120 mesh) to remove any trace impurities.

In conclusion, we have demonstrated herein a robust and environmentally benign methodology for N-tert-butyloxycarbonylation of structurally diverse aliphatic and aromatic amines, phenols, alcohols, thiol, chiral amino acids, amino acid esters and amino alcohols without generation of any unwanted side product such as isocyanate, urea, N,N-di-Boc derivative and the optical antipodes. The reaction was developed under solvent-free reaction conditions utilizing easily affordable imidazolium trifluoroacetate protic ionic liquid as an efficient catalyst. This strategy is high efficient, inexpensive, operational simple, chemo-selective, catalyst recyclable and green which is an outstanding alternative to the commonly used base catalyzed methods using objectionable and toxic organic bases (TEA, DIPEA, DMAP, etc.) and solvents.

Acknowledgements

We are pleased to acknowledge the financial support from Department of Science & Technology (DST), Govt. of India (grant no. SR/S1/OC-49/2010) for this investigation. J. D. is thankful to Tripura University, India for providing RET fellowship.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra02670e

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