A Brønsted Acidic Deep Eutectic Solvent for N-Boc Deprotection

Abstract

The tert-butyloxycarbonyl (Boc) group is one of the most widely used amine-protecting groups in multistep reactions in synthetic organic chemistry as well as in peptide synthesis. Traditional methods to remove the Boc group have disadvantages in terms of high acidity, the use of expensive reagents, excessive amounts of catalysts and harmful solvents as well as high temperatures, making them environmentally unsustainable. Therefore, more efforts must be stepwise tightened to make Boc removal practical, clean, and minimize any potential impact. We describe an efficient and sustainable method for N-Boc deprotection by means of a choline chloride/p-toluenesulfonic acid deep eutectic solvent (DES), which is used as a reaction medium plus catalyst. The adopted conditions allow the deprotection of a wide variety of N-Boc derivatives in excellent yields. The strategy has found advantages in greening, simplicity, and short reaction times, resulting in a useful alternative to standard methods.

1. Introduction

Over the last few decades, the chemical sector, in line with the European plan that aims to become the first continent in the world with zero climate impact, behind the name of Green Chemistry, has faced the concept of “sustainable chemistry”, with the aim to eliminate, or at least decrease, the use of potentially dangerous substances, harmful both to the environment and to human health [1]. To this end, 12 guiding principles have been enunciated that accompany the chemists to orient themselves towards a “green” synthetic design [2].

More recently, these principles have also been established in the pharmaceutical industry. In this regard, the ACS Green Chemistry Institute^® Pharmaceutical Roundtable (GCIPR) (Washington, DC, USA) [3] has produced a Reagent Guide to inform and guide chemists towards greener reagents for various chemical transformations. In particular, GCIPR has identified among its priority research areas for the pharmaceutical sector the development of general methods for the removal of the Boc protecting group (Figure 1). It is a widely used amino protecting group due to its inertia toward catalytic hydrogenolysis, the induction of favorable solubility characteristics, and resistance to hydrolysis under basic conditions and nucleophilic reagents, making it useful when a condition of orthogonality between protective groups is required [4,5]. Given these advantageous characteristics, several amines, amino acids, and peptide synthons supplied to the pharmaceutical industry are sold BOC-protected [6].

Various experimental procedures for Boc-deprotection have been developed that generally involve the use of strong acids, such as phosphoric acid [7,8], HCl [9,10], H₂SO₄ [11], Lewis acids [12,13,14] or basic conditions [15,16]. These methods present several disadvantages in terms of their high acidity, use of expensive reagents, excessive amounts of catalysts and organic solvents, low chemoselectivity, high temperatures, as well as catalyst recovery problems [17]. Trifluroacetic acid (TFA) still represents the reagent of choice to remove the Boc group; however, even this approach has disadvantages as it is toxic, volatile, corrosive, and not environmentally friendly [18,19]. It is an extremely corrosive compound and relatively expensive, especially when it is used in solid-phase peptide synthesis, which requires large quantities of this material.

Therefore, the main “Green Criteria” requires the replacement of conventional solvents and reagents that present important safety as well as the reduction in hazardous waste to a minimum [20,21,22]. The development of an environmentally benign, atom-economic, and sustainable method in the Boc-deprotection still remains a contemporary challenge in synthetic chemistry and the chemical industry.

In this regard, G. Wang et al. described the use of supercritical water under pressure as a medium for the N-Boc deprotection of both aromatic and aliphatic N-Boc amines [23,24]. However, the methodology was characterized by long reaction times and showed incompatibility with the ester functionality. Additionally, an ionic liquid has been proposed as a reaction medium for the N-Boc deprotection strategy [25]. Nevertheless, the addition of a water–dioxane mixture to solubilize the substrates, as well as high reaction temperatures, were required. More recently, Mandal et al. reported a FeCl₃-mediated Boc-deprotection strategy for peptide synthesis both in the solution and in a solid phase [12,13,14]. However, the protocol used dichloromethane (DCM) as the medium and presented limitations related to the recovery step of the Boc cleaved product.

In order to reduce the incidence on the environment of chemical applications, deep eutectic solvents (DESs) have emerged as a step ahead in this field, thanks to their green properties over conventional solvents, such as their negligible vapor pressure, recyclability, and modulation of properties [26,27,28,29]. In this regard, a recent and very interesting trend is the employment of DESs as actual reactive components. Reactive deep eutectic solvents (RDESs) provide a reaction medium containing one or more reaction reagents or a catalyst, which results in numerous advantages, including minimizing waste formation, improving the atom economy of the process, as well as the efficient separation of the final products by precipitation and enhancing the overall process yield [30,31,32,33,34,35]. Given the following advantages, the use of neoteoric solvents, such as DESs, in deprotection reactions could gain much importance in sustainable development chemistry.

Herein, we demonstrated a very simple method of cleavage by employing a DES composed of p-toluenesulfonic acid monohydrate (pTSA) and choline chloride (ChCl), which was used simultaneously as a reaction medium and catalyst.

In choosing the best synthetic route for Boc deprotection that meets the criteria required by Green Chemistry, the Pharmaceutical Roundtable of the ACS Green Chemistry Institute has furnished a Guide to Reagents with the aim of guiding the researcher to use more sustainable reagents [36]. The choice of the most suitable reagent was summarized in a Venn Diagram, in which each circle represented a criterion, namely: ‘Scalability’, ‘Greenness,’ and ‘Wide utility’. The ideal reagent should have all three characteristics, and therefore, should be located in the center, between the intersections of the circles. According to this reagent guide, p-toluenesulfonic acid (pTSA) represents the best alternative to TFA for an eco-friendly Boc-deprotection procedure as it is cheap, readily available, and also biodegradable. It is a Brønsted acid catalyst largely investigated for several reactions, given its strong acidity [37,38,39,40]. The use of a DES containing pTSA as a component makes the entire procedure more efficient for the cleavage at room temperature of various amines, amino acid methyl esters, and dipeptides in short reaction times [41,42,43]. In addition, the use of p-toluenesulfonic acid in the DES form allows disadvantages to be overcome, such as its deliquescent behavior and difficulty of recovery.

2. Results and Discussion

The main goal of our study was to present a simple and cost-effective approach to the deprotection of protected N-Boc derivatives that leads to the corresponding deprotected products with high purities and high yields without the need to apply post-reaction purification. Since the selective deprotection of the Boc group is conducted under mildly acidic conditions, we tested the catalytic behavior of different Brønsted acid and Lewis acid-type DESs. In particular, the quaternary ammonium salt choline chloride (ChCl) has been used as HBA since it is an economic, biodegradable, nontoxic, and even edible quaternary salt that can be extracted from biomass or easily synthesized from fossil reserves [44], whereas pTSA, oxalic acid, citric acid, malonic acid, succinic acid, and FeCl₃ were chosen as HBDs and catalysts (Table 1).

All RDESs have been prepared by using a defined protocol based on mixing the components in a defined molar ratio and then heating at 60–80 °C for 2 h, under constant stirring in a round bottom flask, until a stable homogeneous colorless liquid phase was formed [45]. After the preparation, the DESs were cooled to room temperature and kept closed at room temperature. The DESs were confirmed by Infrared Spectrophotometry (FT-IR) and differential scanning calorimetry (DSC) analysis. Our data matched those available from the literature [21,22].

All the prepared RDESs were tested on the deprotection of N-Boc-benzylamine (1a), selected as a model substrate, and the reaction progress was followed by the TLC and GC/MS analysis of crude reaction mixtures. The results of the development and optimization of the deprotection studies are displayed in Table 1. For a systematic study of the action of the investigated systems, all reactions were conducted at room temperature, except in the case of the DES, which was prepared using citric acid and required a temperature of 50 °C due to its high viscosity that limited the application as a reaction medium. The times shown in the table refer to the respective points of maximum conversion in the substrate, as verified by GC/MS. To our delight, on the treatment of N-Boc benzylamine (1 mmol) with 1 mL of ChCl: pTSA (1:1) at room temperature, the deprotection was smoothly accomplished after only 10 min in a 98% yield, and the free amine was detected by GC-MS after aqueous work-up (Table 1, entry 1).

Otherwise, when the model reaction was screened in the other Brønsted acid and Lewis acid type DESs, 2a was produced in lower yields (entries 2–6, Table 1). More specifically, by performing the same procedure in oxalic acid-based DES (entry 2, Table 1), the deprotection of the amine was achieved in a 58% yield after 30 min. At the same time, using other DESs based on Brønsted acids (entries 3–5, Table 1), a drastic decrease in yield was observed, even when increasing the reaction time. This is probably related to the lower acidic character of the acids used compared to the first mentioned. In the case of the citric acid-based DES, the poor yields observed were probably justified by the highly viscous medium, which did not allow an easy handle of the compound. When the deprotection process was performed in FeCl_3-based Lewis acid DES (entry 6, Table 1), amine deprotection was obtained in a 62% yield after 15 min, confirming the already present literature data that demonstrate its suitability as a catalyst in this transformation, also because it is economic and sustainable [12,13,14]. However, as previously reported, the employment of FeCl₃ makes the work-up procedure more complicated as a large amount of the deprotected compound went into the water with iron during the work-up. An example of the Boc-deprotection protocol carried out with p-toluensulfonic acid was reported by Stone et al. [46]. Nevertheless, N-deprotection occurred after 60 min in a mixture of dichloromethane/tetrahydrofuran (DCM/THF), and the purification procedures were very difficult.

Encouraged by our preliminary results, we next examined the scope and limitations of our method on a variety of aliphatic and aromatic N-tert butylcarbamates. The generality of this procedure is shown in Table 2, exhibiting the efficient deprotection of various classes of nitrogen-containing functional groups (primary and secondary amines, anilines, etc.). All substrates display quantitative isolated yields after reaction times varying from 10 to 30 min.

In particular, N-Boc-protected 2-phenylethylamine (1b) easily undergoes deprotection under the selected reaction conditions to afford the desired amine in an excellent yield (entry 1, Table 2). The removal of the Boc group works well even in the case of N-Boc-aniline (1c) and its substituted derivatives (entries 2–6, Table 2). More specifically, the deprotection reaction of 1c proceeded in 10 min, unlike its derivatives like N-Boc toluidine (1d) and N-Boc anisidine (1e), which required shorter reaction times (both 8 min), probably for the effect of the electron-donating substituents present in para position to the amino function. N-Boc 3-nitroaniline (1f) underwent deprotection within 20 min, probably due to the presence of the nitro electron withdrawing group, which reduced the reactivity of the molecule.

Next, the method was also successfully applied to the deprotection of several N-Boc-protected aliphatic amines. As shown in the Table, cyclic and aliphatic primary amines (entries 7–12, Table 2) can be fully deprotected within 10–20 min. At the same time, when the protocol was applied to secondary Boc-protected amines (entries 14–15, Table 2), the free amines were obtained in excellent yields after 30 min.

The secondary heterocyclic amine, such as N-Boc piperidine (2h), underwent deprotection in 15 min in an almost quantitative yield. The deprotection of N-Boc 4pyridin-4-amine (2f) required a longer reaction time, about 20 min, and this behavior could be explained by the fact that the nitrogen of the heterocyclic ring was protonated by the DES, also leading to a decrease in the yield. N-Boc ethylbenzylamine (1n) afforded the unmasked amine in 30 min and with a 70% yield, while the presence of the isopropyl group in the secondary amine N-Boc isopropyl benzylamine (1o) led to a reduction in the yield (56%), probably due to the steric hindrance that the isopropyl group obtains from the molecule.

An important advantage of the protocol is the simplicity of the recovery of the reaction products. The deprotected substrates can be isolated directly from the reaction mixture as tosylate salts just by washing them with water, followed by recrystallization from ethyl acetate (AcOEt). Free substrates were instead obtained by a simple workup that involved the addition of an aqueous solution of sodium bicarbonate NaHCO₃ (5%). The crude material was then extracted with AcOEt (3 × 5 mL). In both cases, no tedious chromatographic purification was required. All the known compounds had spectroscopic data identical to those reported in the literature [21,22].

Considering the great scientific and industrial value of N-Boc protection in peptide synthesis, we next investigated the N-Boc deprotection of different amino acid derivatives.

For this purpose, some methyl esters of amino acids have been preliminarily protected on the α-amino function with the protecting group Boc. As shown in Table 3, methyl esters of amino acids have aliphatic side chains such as l-Alanine methyl ester and D-Alanine methyl ester, which underwent deprotection in just 10 min and both with yields greater than 98% (entry 1,2, Table 3). Esters are compatible with the reaction conditions (entries 1–5, entry 7, Table 3). In each example, no product resulting from the degradation of methyl esters was observed. The selectivity of deprotection was confirmed in the ¹H NMR spectrum by the presence of a methyl ester group signal at about 3.70 ppm. Branched-chain amino acid methyl esters, such as N-Boc l-Leucine and N-Boc Valine, required longer deprotection times, of about 25 min, with lower yields with respect to amino acids with aliphatic side chains; in particular, leucine was obtained with a yield of 68%, and valine with a yield of 63%, probably both due to the steric hindrance of their side chains (entries 3–4, Table 3).

It was important, at this point, to verify whether the reaction conditions adopted could make the strategy orthogonal, that is, without affecting other protecting groups present in the side chains of the amino acids. Substrates bearing acid-labile protecting groups, such as benzyl ether, remained stable under our conditions. In this regard, we have chosen as substrate the O-Benzyl-L-tyrosine methyl ester since the Boc/Bn strategy, where the Boc group was used as a temporary protecting group of the amino function and Bn (benzyl) of the side chains of the amino acids, is one of the most widely used protection strategies in peptide synthesis [47].

In particular, the α-amino function of the O-benzyl-tyrosine methyl ester was protected with the Boc protecting group, and subsequently, its deprotection was carried out in DES ChCl:pTSA (entry 5, Table 3). In this case, the Boc-group was removed selectively without affecting the O-benzyl ether protection, as proven by the GC/MS and NMR analysis (see Supplementary Information).

The Fluorenylmethyloxycarbonyl (Fmoc) and Boc protecting groups are widely used in peptide synthesis, and therefore, it is of great importance to developing conditions that successfully remove the Boc protecting group while leaving the Fmoc protection unchanged [48,49,50,51,52]. To this aim, the stability of the Fmoc group present in the tryptophan side chain was evaluated (entry 6, Table 3), and it was shown that Fmoc was well tolerated under the reaction conditions adopted. Finally, the preparation of the dipeptide N-Boc-l-Phenylalanyl-l-Alanine methyl ester allowed us to explore the possible extension of the protocol for the deprotection of the amino function of a dipeptide. The dipeptide under consideration underwent the deprotection reaction in Bronsted acidic DES ChCl:pTSA within 15 min (entry 8, Table 3). The removal of the Boc protecting group was monitored by TLC and GC/MS (see Supplementary Materials) analysis from which it was shown that cleavage occurred in the yields demonstrating the high advantage of the DES in this protocol.

Even in the case of deprotection reactions carried out on amino acid systems and the dipeptide, the final products were recovered by a simple work-up operation without the need for any chromatographic purification. To obtain the amino acid or dipeptide not charged and neutralized, a saturated aqueous solution of NaHCO₃ was added and extracted with ethyl acetate and was subsequently washed with brine. The combined organic layers were dried on magnesium sulphate (MgSO₄), filtered, and vacuum-evaporated to provide the raw product in quantitative yield. All the compounds obtained have been characterized by GC/MS and NMR and show spectroscopic data comparable to those reported in the literature [21,22,51].

Based on the previously reported literature [53,54], a plausible mechanistic pathway for Boc-cleavage has been hyphotized (Scheme 1). At first, the Bronsted acidic site of the CHCl:pTSA DES activated the carbamate oxygen by protonation, therefore, weakening and breaking the C=O bond causing the loss of the t-butyl carbocation. The reversible hydrogen bonding between the DES and the substrate made it so that the resultant carbamic acid underwent proton transfer followed by decarboxylation to provide the deprotected amine salt. The final basic workup affords the free amine.

Finally, the feasibility of the developed method was evaluated for a somewhat scaled-up (on the gram scale) experiment with the model substrate N-Boc benzylamine. Even in this case, the reaction proceeded smoothly, affording the desired free amine in 94% of yields, almost similar in all respects to the 1 mmol scale entry (Table 1, entry 1). These results highlighted the efficiency of the RDES for large-scale production as well.

To understand the efficiency of our protocol with respect to conventional methods already reported in the literature for the deprotection of the Boc group, we calculated the process mass intensity (PMI) and complete environmental factor (E-factor). These two metrics are key mass-based metrices useful for the evaluation of the greenness of a synthetic process. [55,56,57]: The E-Factor takes into account waste byproducts, solvent losses, and anything else that can be regarded as a waste; PMI, instead, takes into account the mass of all the material used in a synthetic process relative to the amount of the final product. Table 4 shows the two metrics calculated for our procedure and compares them with those of other reported methodologies.

The PMI and E-factor for our procedure were calculated as 68 and 67, respectively, whereas those for the other procedures were found to be higher (see supporting information for calculation). Nevertheless, the ideal E factor is 0, and higher E factors are relatively less amenable. However, it matters what kind of wastes are produced because, in our protocol, choline chloride and p-toluensulfonic acid may be of little concern compared to toxic organic volatile solvents and corrosive acids. Therefore, these data indicate the feasibility, greenness, and sustainability of our process.

3. Materials and Methods

3.1. General Informations

Commercially available reagents were purchased from Sigma-Aldrich Chemical Co. (Milano, Italy) and used as supplied unless stated otherwise. All syntheses were carried out in atmospheric conditions. The ¹H NMR and ¹³C NMR spectra were recorded at 300 MHz. Spectral analysis was performed at 293 K on the diluted solutions of each compound by using CDCl₃ as the solvent. Chemical shifts (δ) are reported in ppm and referenced to CDCl₃ (7.25 ppm for ¹H and 77.0 ppm for ¹³C spectra). Coupling constants (J) are reported in hertz (Hz). Reaction mixtures were monitored by thin layer chromatography (TLC) using Merck Silica gel 60-F254 precoated glass plates or 0.2% ninhydrin in ethanol. GC-MS analyses were carried out using a 30 m HP-35MS capillary column with a 0.25 mm internal diameter and a 0.25 μm film thickness. The mass detector was operated in the electron impact ionization mode (EI-MS) at an electron energy of 70 eV. He was used as the carrier gas. The injection port was heated to 250 °C. The oven temperature program was initially set at 50 °C and held for 2 min, then was ramped to 280 °C at a rate of 14 °C/min and maintained at 280 °C for a further 10 min.

3.2. Preparation of DESs

DESs were prepared following the heating method [58]. First, choline chloride was dried in a high vacuum pump at 50 °C for 1 day, while the hydrogen bond donors (pTSA, oxalic acid, citric acid, malonic acid, succinic acid, and FeCl₃) were used without any further purification (Table 5). The hydrogen bond acceptor (HBA) and hydrogen bond donors (HBDs) at a proper molar ratio (1:1) were placed in a glass screw cap vial and were heated to 60–70 °C under a constant stirring speed of 100 rpm by using a heating plate (Bibby Scientific Limited, Beacon Road, Stone, Staffordshire, UK) until a homogeneous clear liquid was formed.

3.3. General Procedure for the N-Boc Deprotection of Amines and Amino Acid Derivatives

In a 10 mL round-bottomed flask, 1 mL of DES (ChCl:pTSA) was maintained under stirring, and an N-Boc-protected amine or N-Boc-protected amino acid derivative (1 mmoL) was added. The mixture was allowed to stir at room temperature. TLC and GC/MS were used to monitor the reaction. Upon completion of the reaction, an aqueous solution of sodium bicarbonate NaHCO₃ (5%) was added. The crude material was then extracted with AcOEt (3 x 5 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and finally concentrated under a low vacuum using a rotary evaporator to yield the pure deprotected amine. Spectroscopic data (GC-MS, ¹H-NMR e ¹³C-NMR) were compared to those of the pure products. The obtained spectroscopic data are in agreement with the literature data [21,22,51].

3.3.1. Benzylamine (2a)

¹H NMR (300 MHz, CDCl₃) δ 7.40–7.20 (m, 5H, ArH), 3.86 (s, 2H), 1.53 (2, 2H, NH₂). ¹³C NMR (75 MHz, CDCl₃) δ 143.3, 129.1, 127.7, 126.9, 46.5. GC/MS (EI): m/z (%) 107 (M⁺) (59), 106 (100), 91 (14), 79 (43), 77 (25), 65 (7), 51 (17).

3.3.2. 2-Phenylethylamine (2b)

¹H NMR (300 MHz, CDCl₃) δ 7.32–7.18 (m, 5H, ArH), 2.94 (t, 2H, J = 6.7 Hz, CH2), 2.72 (t, 2H, J = 6.7 Hz, CH2), 1.24 (s, 2H, NH2) ppm. ¹³C NMR (75 MHz, CDCl₃) δ 139.9, 128.8, 128.0, 126.2, 42.8, 39.4. GC/MS (EI): m/z (%) 121 (M⁺) (23), 117 (5), 103 (9), 91 (100), 77 (18), 65 (48), 51 (25), 41 (7).

3.3.3. Aniline (2c)

¹H NMR (300 MHz, CDCl₃) δ 7.24–7.12 (m, 3H), 6.77–6.65 (m, 2H), 3.61 (br s, 2H, NH2) ppm. ¹³C NMR (75 MHz, CDCl₃) δ 132.8, 130.2, 128.2, 123.5. GC/MS (EI): m/z (%) 93 (M⁺) (100), 92 (13), 66 (42), 65 (23), 52 (5).

3.3.4. p-Toluidine (2d)

¹H NMR (300 MHz, CDCl₃) δ 6.94 (d, 2H, J = 8.4 Hz, ArH), 6.60 (d, 2H, J = 8.4, ArH), 3.32 (br s, 2H, NH₂), 2.23 (s, 3H, CH₃) ppm. GC/MS (EI): m/z (%) 107 (M⁺) (68), 106(100), 91 (4), 77 (18), 63 (4), 52 (9), 41 (4).

3.3.5. p-Anisidine (2e)

¹H NMR (300 MHz, CDCl₃) δ 6.77 (d, 2H, J = 8.4 Hz, ArH), 6.66 (d, 2H, J = 8.4 Hz, ArH), 3.78 (s, 3H, OMe), 3.41 (s, 2H, NH₂) ppm. ¹³C NMR (75 MHz, CDCl₃) δ 152.8, 140.0, 116.0, 114.8, 55.6. GC/MS (EI): m/z (%) 123 (M⁺) (62), 108 (100), 95 (4), 80 (48), 65 (8), 53 (19), 41 (4).

3.3.6. Pyridin-4-amine (2f)

¹H NMR (300 MHz, CDCl₃) δ 8.29 (d, 2H, J = 5.1 Hz, ArH), 7.02 (d, 2H, J = 5.1 Hz, ArH), 3.68 (s, 2H, CH₂), 1.37 (s, 2H, NH2) ppm. ¹³C NMR (75 MHz, CDCl₃) δ 151.8, 129.4, 121.8, 44.7. GC/MS (EI): m/z (%) 108 (M⁺) (24), 107 (25), 92 (4), 80 (100), 79 (26), 65 (6), 51 (17), 40 (3).

3.3.7. 3-Nitroaniline (2g)

¹H NMR (300 MHz, CDCl₃) δ 7.60 (d, 1H, J = 8.1 Hz, ArH), 7.45 (s, 1H, ArH), 7.29 (m, 1H, ArH), 6.96 (d, 1H, J = 7.8 Hz, ArH), 4.00 (br s, NH₂) ppm. GC/MS (EI): m/z (%) 138 (M⁺) (75), 122 (4), 108 (5), 92 (85), 80 (10), 65 (100), 52 (12), 39 (25).

3.3.8. Piperidine (2h)

¹H NMR (300 MHz, CDCl₃) δ 2.80–2.77 (M, 4H, NHCH₂, NHCH₂), 2.12 (S, 1H, NH), 1.53–1.50 (M, 6H, (CH₂)₃) ppm. GC/MS (EI): m/z (%) 85 (M⁺) (50), 84 (100), 70 (11), 57 (30), 56 (49).

3.3.9. Allylamine (2i)

¹H NMR (300 MHz, CDCl₃) δ 5.78–5.65 (m, 1H, CH), 4.90 (m, 1H, CH₂), 4.79 (m, 1H, CH₂), 3.06 (d, 2H, J = 5.4 Hz, CH₂), 1.02 (s, 2H, NH₂) ppm. ¹³C NMR (75 MHz, CDCl₃) δ 139.6, 113.2, 44.5.

3.3.10. Cyclopentylamine (2j)

¹H NMR (300 MHz, CDCl₃) δ 3.31 (m, 1H, CH), 1.80–1.68 (m, 4H, CH₂, CH₂), 1.60–1.59 (m, 2H, CH₂), 1.57–1.51 (m, 2H, CH₂), 1.32–1.21 (m, 2H, NH₂) ppm. GC/MS (EI): m/z (%) 85 (M⁺) (12), 67 (4), 56 (100), 43 (12).

3.3.11. Pentylamine (2k)

¹H NMR (300 MHz, CDCl₃) δ 2.61 (t, 2H, J = 6.9 Hz, CH₂), 2.16 (s, 2H, NH₂), 1.43–1.34 (m, 2H, CH₂), 1.32–1.24 (m, 4H, CH₂), 0.85 (t, 3H, J = 6.7 Hz, CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃) δ 41.9, 33.1, 28.9, 22.4, 13.9. δ GC/MS (EI): m/z (%) 87 (M⁺) (98), 69 (10), 58 (5), 55 (23), 51 (5), 45 (70), 41 (91), 30 (100).

3.3.12. (R)-1-Phenylethylamine (2l)

¹H NMR (300 MHz, CDCl₃) δ 7.51–7.22 (m, 5H, ArH), 4.10 (q, 1H, J = 13.4 and J = 6.6 Hz, CH), 2.15 (s, 2H, NH2), 1.57 (d, 3H, J = 6.6 Hz, CH3) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 147.6, 129.4, 126.9, 125.9, 51.4, 25.5. GC/MS (EI): m/z (%) 121 (M⁺) (1), 120 (6), 106 (100), 103 (4), 79 (30), 77 (24), 51 (10).

3.3.13. (S)-1-Phenylethylamine (2m)

¹H NMR (300 MHz, CDCl₃) δ 7.31–7.22 (m, 5H, ArH), 4.10 (q, 1H, J = 13.2 J = 6.6 Hz, CH), 2.05 (s, 2H, NH₂), 1.57 (d, 3H, J = 6.6 Hz, CH3) ppm. ¹³C NMR (75 MHz, CDCl₃) δ 174.6, 129.4, 126.9, 125.8, 51.4, 25.4. GC/MS (EI): m/z (%) 121 (M⁺) (1), 120 (6), 106 (100), 103 (4), 79 (30), 77 (25), 51 (10).

3.3.14. Ethyl Benzylamine (2n)

¹H NMR (300 MHz, CDCl₃) δ 7.40–7.25 (m, 5H, ArH), 3.79 (s, 2H, CH₂Ph), 2.74–2.67 (q, 2H, J = 7.1 Hz, CH₂CH₃), 1.54 (s, 1H, NH), 1.16 (t, 3H, J = 7.2 Hz) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 140.5, 128.3, 127.2, 126.8, 53.7, 43.6, 15.2. GC/MS (EI): m/z (%) 135 (M⁺) (13), 134 (15), 120 (32), 92 (6), 91 (100), 79 (6), 65 (13), 58 (15), 51 (5).

3.3.15. N-Isopropylbenzylamine (2o)

¹H NMR (300 MHz, CDCl₃) δ 7.36–7.27 (m, 5 H, ArH), 3.81 (s, 2H, CH₂), 2.89 (q, 1H, J = 6.2 Hz, CH), 1.33 (s, 1H, NH), 1.29 (d, 6H, J = 6.3 Hz, CH(CH₃)₂) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 140.8, 128.5, 127.5, 127.4, 50.6, 48.1, 23.5. GC/MS (EI): m/z (%) 149 (M⁺) (4), 134 (42), 106 (4), 92 (5), 91 (100), 77 (5), 65 (11), 51 (5).

3.3.16. l-Alanine Methyl Ester (2p)

¹H NMR (300 MHz, CDCl₃) δ 8.70–8.61 (m, 2H, NH₂), 4.30 (m, 1H, -CH), 3.81 (s, 3H, OMe), 1.74 (d, 3H, J = 7.2 Hz, CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 170.6, 52.9, 49.5, 16.0. GC/MS (EI): m/z (%) 103 (M⁺) (3), 88 (5), 59 (3), 44 (100), 40 (5), 32 (22).

3.3.17. d-Alanine Methyl Ester (2q)

¹H NMR (300 MHz, CDCl₃) δ 8.70–8.61 (m, 2H, NH₂), 4.30 (m, 1H, α-CH), 3.81 (s, 3H, OMe), 1.74 (d, 3H, J = 7.2 Hz, CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 170.6, 52.9, 49.5, 16.0. GC/MS (EI): m/z (%) 103 (M⁺) (2), 88 (5), 59 (3), 44 (100), 40 (5). GC/MS (EI): m/z (%) 103 (M⁺) (2), 88 (5), 59 (3), 44 (100), 40 (5).

3.3.18. l-Valine Methyl Ester (2r)

¹H NMR (300 MHz, CDCl₃) δ 8.82 (m, 2H, NH₂), 3.97 (m, 1H, -CH), 3.81 (s, 3H, OMe), 2.49 (m, 1H, CH), 1.17–1.14 (m, 6H, (CH₃)₂) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 168.8, 58.6, 52.7, 29.9, 18.3. GC/MS (EI): m/z (%) 131 (M⁺) (3), 88 (32), 72 (100), 55 (36), 41 (10).

3.3.19. l-Leucine Methyl Ester (2s)

¹H NMR (300 MHz, CDCl₃) δ 8.90–8.75 (br s, 2H, NH₂), 4.12 (m, 1H, α-CH), 3.81 (s, 3H, OCH₃), 2.10–1.82 (m, 3H, CH₂ and CH(CH₃), 1.03 (d, 6H, CH(CH₃)₂) ppm. GC/MS (EI): m/z (%) 145 (M⁺) (2), 130 (3), 86 (100), 70 (3), 44 (56).

3.3.20. O-Benzyl-l-Tyrosine Methyl Ester (2t)

¹H NMR (300 MHz, CDCl₃) δ 7.89 (brs, 2H, NH₂), 7.46–7.21 (m, 5H, ArH), 7.10–6.99 (m, 2H, ArH), 6.95–6.82 (m, 2H, ArH), 5.08 (s, 2H, OCH₂), 3.79 (m, 1H, a-CH), 3.61 (s, 3H, OMe), 2.72 (m, 2H, CH₂Ph) ppm. GC/MS (EI): m/z (%) 285 (M⁺) (4), 226 (7), 197 (30), 135 (2), 107 (7), 91 (100), 77 (4), 65 (8), 51 (2).

3.3.21. Nα-Fmoc-Tryptophane (2u)

¹H NMR (300 MHz, DMSO-d₆) δ 8.08 (d, 1H, J = 7.5 Hz, NH), 7.73–7.71 (m, 3H, ArH), 7.56–7.16 (m, 10 H), 5.33 (m, 1H, α-CH), 4.43–4.18 (m, 3H, CH, CH₂-Fmoc), 3.83 (m, 2H, CH₂-Trp) ppm.

3.3.22. l-Phenylalanyl-l-Alanine Methyl Ester (2v)

¹H NMR (300 MHz, CDCl₃) δ 7.23–7.15 (m, 5H, ArH), 6.70 (br s, 1H, OCONH), 5.14 (d, 1H, J = 8.2 Hz, NHCHCH3), 4.47 (m, 1H, α–CHAla); 4.38 (m, 1H, α–CHPhe), 3.66 (s, 3H, OMe), 3.09–2.92 (m, 2H, CH2Ph), 1.15 (d, 3H, J = 7.2 Hz, CHCH3) ppm. GC/MS (EI): m/z (%) 191 (M^+. –59), 159 (14), 127 (4), 120 (100), 99 (16), 91 (14), 77 (7), 65 (5), 51 (3).

4. Conclusions

In summary, we have reported a highly efficient protocol for the deprotection of Boc protecting groups by using PTSA-based RDES as both a medium and catalyst. This sets the stage for the selective deprotection of a wide variety of N-Boc derivatives in high yields with excellent purities by a simple workup. The developed strategy displays a broad substrate scope in the case of structurally different amines, amino acids, and dipeptides. Mild reaction conditions, operational simplicity, as well as the absence of tedious purification procedures, and clean reaction profiles represent advantages that underline the possibility of using this procedure as a cost-effective and environmentally friendly alternative to classical strategies.

Author Contributions

Conceptualization, D.P. and M.L.D.G.; Data curation, C.S.; Formal analysis, D.P., C.S., S.T. and R.C.; Funding acquisition, C.S.; Investigation, D.P. and R.D.R.; Project administration, M.L.D.G.; Resources, S.T. and R.C.; Supervision, M.L.D.G.; Visualization, C.S., S.T. and R.C.; Writing—Original draft, D.P.; Writing—Review and editing, M.L.D.G. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

Data are available upon request.

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figure, Scheme and Tables

Figure 1. Chemical structure of Boc-protecting group.

Scheme 1. Proposed mechanism for Boc-deprotection in RDES.

Table 1

Optimization of conditions for the cleavage of N-Boc protecting group.

Scheme 1. Proposed mechanism for Boc-deprotection in RDES.
Entry	DES (1:1 Molar Ratio)	Temp. (°C)	Time b (min.)	Yield (%)
1	ChCl: pTSA	25	10	98
2	ChCl: oxalic acid	25	30	58
3	ChCl: citric acid	50 a	30	15
4	ChCl: malonic acid	25	60	26
5	ChCl: succinic acid	25	60	20
6	ChCl: FeCl3	25	15	62

^a Reaction conducted at 50 °C due to the high viscosity of the investigated DES; ^b Times refer to the respective points of maximum conversion of the substrate, according to GC/MS.

Table 2

Scope for the deprotection of N-Boc amines ^a.

[Image omitted. Please see PDF.]
Entry	N-Boc-amine	Product	Time (min)	Yield (%) b
1	[Image omitted. Please see PDF.] 1b	[Image omitted. Please see PDF.] 2b	10	>98
2	[Image omitted. Please see PDF.] 1c	[Image omitted. Please see PDF.] 2c	10	>98
3	[Image omitted. Please see PDF.] 1d	[Image omitted. Please see PDF.] 2d	15	>98
4	[Image omitted. Please see PDF.] 1e	[Image omitted. Please see PDF.] 2e	15	>98
5	[Image omitted. Please see PDF.] 1f	[Image omitted. Please see PDF.] 2f	20	90
6	[Image omitted. Please see PDF.] 1g	[Image omitted. Please see PDF.] 2g	20	86
7	[Image omitted. Please see PDF.] 1h	[Image omitted. Please see PDF.] 2h	15	>98
8	[Image omitted. Please see PDF.] 1i	[Image omitted. Please see PDF.] 2i	10	>98
9	[Image omitted. Please see PDF.] 1j	[Image omitted. Please see PDF.] 2j	10	>98
10	[Image omitted. Please see PDF.] 1k	[Image omitted. Please see PDF.] 2k	10	>98
11	[Image omitted. Please see PDF.] 1l	[Image omitted. Please see PDF.] 2l	20	>98
12	[Image omitted. Please see PDF.] 1m	[Image omitted. Please see PDF.] 2m	20	>98
13	[Image omitted. Please see PDF.] 1n	[Image omitted. Please see PDF.] 2n	25	70
14	[Image omitted. Please see PDF.] 1o	[Image omitted. Please see PDF.] 2o	30	56

^a Reaction conditions: all reactions were carried out by using 1 mmol of N-Boc amine in 1 mL of ChCl: pTSA at rt for the time reported above. ^b Isolated yields after work-up.

Table 3

DES-catalyzed deprotection of N-Boc amino acid derivatives and N-Boc dipeptide ^a.

[Image omitted. Please see PDF.]
Entry	N-Boc-amino Acid	Product c	Time (min.)	Yield (%) b
1	[Image omitted. Please see PDF.] 1p	[Image omitted. Please see PDF.] 2p	10	>98 d
2	[Image omitted. Please see PDF.] 1q	[Image omitted. Please see PDF.] 2q	10	>98 d
3	[Image omitted. Please see PDF.] 1r	[Image omitted. Please see PDF.] 2r	20	63
4	[Image omitted. Please see PDF.] 1s	[Image omitted. Please see PDF.] 2s	15	68
5	[Image omitted. Please see PDF.] 1t	[Image omitted. Please see PDF.] 2t	35	>98
6	[Image omitted. Please see PDF.] 1u	[Image omitted. Please see PDF.] 2u	40	90
7	[Image omitted. Please see PDF.] 1v	[Image omitted. Please see PDF.] 2v	15	>98

^a Reaction conditions: all reactions were carried out using 1 mmol of Boc-amine in 1 mL of ChCl: the pTSA at rt for the time reported above. ^b Isolated yields after work-up. ^c MS and NMR were used to verify the exact mass and structure of the prepared product. ^d To verify enantiomeric purity, chiral HPLC was performed and compared with the commercially available racemic mixture. A single peak was observed at the corresponding retention time, while the racemic mixture provided two.

Table 4

Calculated green metrics percentage yield, PMI, and E-factor for our Boc deprotection procedure and for already reported methods.

Entry	Solvents and Reagents	Yield (%)	PMI	E-Factor	Ref.
1	THF, aqueous H3PO4	94	91	90	[7]
2	DCM, aqueous H3PO4	91	96	95	[8]
3	DCM, H2SO4	93	383	382	[11]
4	DCM, TFA	98	92	91	[18,19]
5	ChCl:pTSA	98	68	67	Our work

Table 5

Deep eutectic solvents investigated in the present work.

Entry	HBA	HBD	HBA/HBD Molar Ratio	mp HBD (°C)	Tm (°C)	Ref.
1	ChCl	Monohydrated pTSA	1:1	103	37	[42]
2	ChCl	Oxalic acid	1:1	101	34	[58]
3	ChCl	Citric acid	1:1	153	69	[58]
4	ChCl	Malonic acid	1:1	136	10	[59,60]
5	ChCl	Succinic acid	1:1	184	71	[59,60]
6	ChCl	FeCl3	1:1	306	65	[58]

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/catal12111480/s1, The IR spectra of ChCl; pTSA; DES (ChCl:pTSA); General procedures; and ¹H-NMR spectra of some representative synthesized compounds.

References

1. Chen, T.-L.; Kim, H.; Pan, S.Y.; Tsenga, P.C.; Lin, Y.P.; Chiang, P.C. Implementation of green chemistry principles in circular economy system towards sustainable development goals: Challenges and perspectives. Sci. Total Environ.; 2020; 716, 136998. [DOI: https://dx.doi.org/10.1016/j.scitotenv.2020.136998] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32044483]

2. Procopio, D.; Di Gioia, M.L. An Overview of the Latest Advances in the Catalytic Synthesis of Glycerol Carbonate. Catalysts; 2022; 12, 50. [DOI: https://dx.doi.org/10.3390/catal12010050]

3. Anastas, P.; Eghbali, N. Green chemistry: Principles and practice. Chem. Soc. Rev.; 2010; 39, pp. 301-312. [DOI: https://dx.doi.org/10.1039/B918763B]

4. Constable, D.J.C.; Dunn, P.J.; Hayler, J.D.; Humphrey, G.R.; Leazer, J.L.; Linderman, R.J.; Lorenz, K.; Manley, J.; Pearlman, B.A.; Wells, A. et al. Key green chemistry research areas—A perspective from pharmaceutical manufacturers. Green Chem.; 2007; 9, pp. 411-420. [DOI: https://dx.doi.org/10.1039/B703488C]

5. Đud, M.; Margetić, D. Solvent-free mechanochemical deprotection of N-Boc group. IJOC; 2017; 7, pp. 140-144.

6. Di Gioia, M.L.; Barattucci, A.; Bonaccorsi, P.; Leggio, A.; Minuti, L.; Romio, E.; Temperini, A.; Siciliano, C. Deprotection/reprotection of the amino group in α-amino acids and peptides. A one-pot procedure in [Bmim][BF₄] ionic liquid. RSC Adv.; 2014; 6, pp. 2678-2686. [DOI: https://dx.doi.org/10.1039/C3RA46599C]

7. Li, B.; Bemish, R.; Buzon, R.A.; Chiu, C.K.-F.; Colgan, S.T.; Kissel, W.; Le, T.; Leeman, K.R.; Newell, L.; Roth, J. Aqueous phosphoric acid as a mild reagent for deprotection of the t-butoxycarbonyl group. Tetrahedron Lett.; 2003; 44, pp. 8113-8115. [DOI: https://dx.doi.org/10.1016/j.tetlet.2003.09.040]

8. Li, B.; Berliner, M.; Buzon, R.; Chiu, C.K.-F.; Colgan, S.T.; Kaneko, T.; Keene, N.; Kissel, W.; Le, T.; Leeman, K.R. et al. Aqueous phosphoric acid as a mild reagent for deprotection of tert-butyl carbamates, esters, and ethers. Org. Chem.; 2006; 71, pp. 9045-9050. [DOI: https://dx.doi.org/10.1021/jo061377b]

9. Han, G.; Tamaki, M.; Hruby, V.J. Fast, efficient and selective deprotection of the tert-butoxycarbonyl (Boc) group using HCl/dioxane (4 m). J. Pept. Res.; 2001; 58, pp. 338-341. [DOI: https://dx.doi.org/10.1034/j.1399-3011.2001.00935.x]

10. Coffey, D.S.; Hawk, M.K.N.; Ghera, S.J.; Marler, P.G.; Dodson, P.N.; Lytle, M.L. Large Scale Deprotection of a tert-Butoxycarbonyl (Boc) Group Using Aqueous HCl and Acetone. Org. Proc. Res. Dev.; 2004; 8, pp. 945-947. [DOI: https://dx.doi.org/10.1021/op049842z]

11. Strazzolini, P.; Misuri, N.; Polese, P. Efficient cleavage of carboxylic tert-butyl and 1-adamantyl esters, and N-Boc-amines using H₂SO₄ in CH₂C_l2. Tetrahedron Lett.; 2005; 46, pp. 2075-2078. [DOI: https://dx.doi.org/10.1016/j.tetlet.2005.01.129]

12. Giri, R.S.; Roy, S.; Dolai, G.; Manne, S.R.; Mandal, B. FeCl₃-Mediated Boc Deprotection: Mild Facile Boc-Chemistry in Solution and on Resin. ChemistrySelect; 2020; 5, pp. 2050-2056. [DOI: https://dx.doi.org/10.1002/slct.201904617]

13. López-Soria, J.M.; Pérez, S.J.; Hernández, J.N.; Ramírez, M.A.; Martín, V.S.; Padrón, J.I. A practical, catalytic and selective deprotection of a Boc group in N,N′-diprotected amines using iron (III)-catalysis. RSC Adv.; 2015; 5, pp. 6647-6651. [DOI: https://dx.doi.org/10.1039/C4RA12143K]

14. Bose, D.S.; Kumar, K.K.K.; Reddy, A.V.N. A New Protocol for Selective Deprotection of N-tert-Butoxycarbonyl Protective Group (t-Boc) with Sn(OTf)₂. Synth. Commun.; 2003; 33, pp. 445-450. [DOI: https://dx.doi.org/10.1081/SCC-120015775]

15. Tom, N.J.; Simon, W.M.; Frost, H.N.; Ewing, M. Deprotection of a primary Boc group under basic conditions. Tetrahedron Lett.; 2004; 45, pp. 905-906. [DOI: https://dx.doi.org/10.1016/j.tetlet.2003.11.108]

16. Chakrabarty, M.; Kundu, T.; Harigaya, Y. Mild deprotection of tert-butyl carbamates of NH-heteroarenes under basic conditions. Synth. Commun.; 2006; 36, pp. 2069-2077. [DOI: https://dx.doi.org/10.1080/00397910600634480]

17. Cheraiet, Z.; Ouarna, S.; Hessainia, S.; Berredjem, M.; Aouf, N. N-tert-Butoxycarbonylation of Structurally Diverse Amines and Sulfamides under Water-Mediated Catalyst-Free Conditions. ISRN Org. Chem.; 2012; 8, 404235. [DOI: https://dx.doi.org/10.5402/2012/404235] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24052842]

18. Srinivasan, N.; Yurek-George, A.; Ganesan, A. Rapid deprotection of N-Boc amines by TFA combined with freebase generation using basic ion-exchange resins. Mol. Divers.; 2005; 9, pp. 291-293. [DOI: https://dx.doi.org/10.1007/s11030-005-4386-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16311804]

19. Sarko, C.R.; Westbrook, J.; Zhang, Z.; Yu, M.; Hopkins, T.D.; Lowe, M.D. Heterocyclic Carboxylic Acids as Activators of Soluble Guanylate Cyclase. Patent; WO2016014463, 28 January 2016.

20. Cheraiet, Z.; Ouarna, S.; Zoubir, J.; Malika, B.; Nour-Eddine, A. A simple and efficient green method for the deprotection of N-Boc in various structurally diverse amines under water-mediated catalyst-free conditions. Int. J. Chem.; 2012; 4, 73.

21. Verschueren, R.H.; Gilles, P.; Van Mileghem, S.; De Borggraeve, W.M. Solvent-free N-Boc deprotection by ex situ generation of hydrogen chloride gas. Org. Biomol. Chem.; 2021; 19, pp. 5782-5787. [DOI: https://dx.doi.org/10.1039/D1OB00728A] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33973618]

22. George, N.; Ofori, S.; Parkin, S.; Awua, S.G. Mild deprotection of the N-tert-butyloxycarbonyl (N-Boc) group using oxalyl chloride. RSC Adv.; 2020; 10, 24017. [DOI: https://dx.doi.org/10.1039/D0RA04110F]

23. Wang, G.; Li, C.; Li, J.; Ji, X. Catalyst-free water-mediated N-Boc deprotection. Tetrahedron Lett.; 2009; 50, pp. 1438-1440. [DOI: https://dx.doi.org/10.1016/j.tetlet.2009.01.056]

24. Wang, J.; Liang, Y.L.; Qu, J. Boiling water-catalyzed neutral and selective N-Boc deprotection. Chem. Commun.; 2009; 34, pp. 5144-5146. [DOI: https://dx.doi.org/10.1039/b910239f] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20448974]

25. Majumdar, S.; De, J.; Chakraborty, A.; Royb, D.; Maitib, D.K. A protic ionic liquid catalyzed strategy for selective hydrolytic cleavage of tert-butyloxycarbonyl amine (N-Boc). RSC Adv.; 2015; 5, pp. 3200-3205. [DOI: https://dx.doi.org/10.1039/C4RA13419B]

26. Procopio, D.; Siciliano, C.; Trombino, S.; Dumitrescu, D.E.; Suciu, F.; Di Gioia, M.L. Green solvents for the formation of amide linkages. Org. Biomol. Chem.; 2022; 20, pp. 1137-1149. [DOI: https://dx.doi.org/10.1039/D1OB01814K]

27. Trombino, S.; Siciliano, C.; Procopio, D.; Curcio, F.; Laganà, A.S.; Di Gioia, M.L.; Cassano, R. Deep Eutectic Solvents for Improving the Solubilization and Delivery of Dapsone. Pharmaceutics; 2022; 14, 333. [DOI: https://dx.doi.org/10.3390/pharmaceutics14020333]

28. Di Gioia, M.L.; Cassano, R.; Costanzo, P.; Cano, N.H.; Maiuolo, L.; Nardi, M.; Nicoletta, F.P.; Oliverio, M.; Procopio, A. Green synthesis of privileged benzimidazole scaffolds using active deep eutectic solvent. Molecules; 2019; 24, 2885. [DOI: https://dx.doi.org/10.3390/molecules24162885] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31398916]

29. Di Gioia, M.L.; Nardi, M.; Costanzo, P.; De Nino, A.; Maiuolo, L.; Oliverio, M.; Procopio, A. Biorenewable deep eutectic solvent for selective and scalable conversion of furfural into cyclopentenone derivatives. Molecules; 2018; 23, 1891. [DOI: https://dx.doi.org/10.3390/molecules23081891]

30. Perna, F.M.; Vitale, P.; Capriati, V. Deep eutectic solvents and their applications as green solvents. Curr. Opin. Green Sustain. Chem.; 2020; 21, pp. 27-33. [DOI: https://dx.doi.org/10.1016/j.cogsc.2019.09.004]

31. Maiuolo, L.; Russo, B.; Algieri, V.; Nardi, M.; Di Gioia, M.L.; Tallarida, M.A.; De Nino, A. Regioselective synthesis of 1,5-disubstituted 1,2,3-triazoles by 1,3-dipolar cycloaddition: Role of Er(OTf)₃, ionic liquid and water. Tetrahedron Lett.; 2019; 60, pp. 672-674. [DOI: https://dx.doi.org/10.1016/j.tetlet.2019.01.053]

32. Allegretti, C.; Gatti, F.G.; Marzorati, S.; Rossato, L.A.M.; Serra, S.; Strini, A.; D’Arrigo, P. Reactive Deep Eutectic Solvents (RDESs): A new tool for phospholipase D-catalyzed preparation of phospholipids. Catalysts; 2021; 11, 655. [DOI: https://dx.doi.org/10.3390/catal11060655]

33. Ünlü, A.E.; Arikaya, A.; Takaç, S. Use of deep eutectic solvents as catalyst: A mini-review. Green Proc. Synth.; 2019; 8, pp. 355-372. [DOI: https://dx.doi.org/10.1515/gps-2019-0003]

34. Cicco, L.; Dilauro, G.; Perna, F.M.; Vitale, P.; Capriati, V. Advances in deep eutectic solvents and water: Applications in metal-and biocatalyzed processes, in the synthesis of APIs, and other biologically active compounds. Org. Biomol. Chem.; 2021; 19, pp. 2558-2577. [DOI: https://dx.doi.org/10.1039/D0OB02491K] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33471017]

35. Piemontese, L.; Sergio, R.; Rinaldo, F.; Brunetti, L.; Perna, F.M.; Santos, M.A.; Capriati, V. Deep eutectic solvents as effective reaction media for the synthesis of 2-hydroxyphenylbenzimidazole-based scaffolds en route to donepezil-like compounds. Molecules; 2020; 25, 574. [DOI: https://dx.doi.org/10.3390/molecules25030574] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32013037]

36. Bryan, M.C.; Dunn, P.J.; Entwistle, D.; Gallou, F.; Koenig, S.G.; Hayler, J.D.; Hickey, M.R.; Hughes, S.; Kopach, M.E.; Moine, G. et al. Key Green Chemistry research areas from a pharmaceutical manufacturers’ perspective revisited. Green Chem.; 2018; 20, 5082. [DOI: https://dx.doi.org/10.1039/C8GC01276H]

37. Palaniappan, S.; Rajender, B. A Novel Polyaniline-Silver Nitrate-p-Toluenesulfonic Acid Salt as Recyclable Catalyst in the Stereoselective Synthesis of β-Amino Ketones: “One-Pot” Synthesis in Water Medium. Adv. Synth. Catal.; 2010; 352, pp. 2507-2514. [DOI: https://dx.doi.org/10.1002/adsc.201000346]

38. Palaniappan, S.; Rajender, B.; Umashankar, M. Controllable stereoselective synthesis of cis or trans pyrano and furano tetrahydroquinolines: Polyaniline-p-toluenesulfonate salt catalyzed one-pot aza-Diels–Alder reactions. J. Mol. Catal. A Chem.; 2012; 352, pp. 70-74. [DOI: https://dx.doi.org/10.1016/j.molcata.2011.10.014]

39. Rajender, B.; Palaniappan, S. Emeraldine Base form of polyaniline nanofibers as new, economical, green, and efficient catalyst for synthesis of Z-Aldoximes. J. Catal.; 2014; 2014, 515428.

40. Wang, L.; Zhou, M.; Chen, Q.; He, M.-Y. Brønsted Acidic Deep Eutectic Solvent Catalysed the One-Pot Synthesis of 2H-indazolo[2,1-b] Phthalazine-Triones. J. Chem. Res.; 2013; 37, pp. 598-600. [DOI: https://dx.doi.org/10.3184/174751913X13787347508252]

41. Kamarudin, A.F.; Hizaddin, H.F.; El-blidi, L.; Ali, E.; Hashim, M.A.; Hadj-Kali, M.K. Performance of p-Toluenesulfonic Acid–Based Deep Eutectic Solvent in Denitrogenation: Computational Screening and Experimental Validation. Molecules; 2020; 25, 5093. [DOI: https://dx.doi.org/10.3390/molecules25215093]

42. Gutieŕrez-Hernańdez, A.; Richaud, A.; Chacoń-García, L.; Corteś-García, C.J.; Meńdez, F.; Contreras-Celedoń, C.A.J. Deep Eutectic Solvent Choline Chloride/p-toluenesulfonic Acid and Water Favor the Enthalpy-Driven Binding of Arylamines to Maleimide in Aza-Michael Addition. J. Org. Chem.; 2021; 86, pp. 223-234. [DOI: https://dx.doi.org/10.1021/acs.joc.0c02039]

43. Rodriguez, N.R.; Machiels, L.; Binnemans, K. p-Toluenesulfonic acid-based deep-eutectic solvents for solubilizing metal oxides. ACS Sustain. Chem. Eng.; 2019; 7, pp. 3940-3948. [DOI: https://dx.doi.org/10.1021/acssuschemeng.8b05072]

44. Zhang, Q.; De Oliveira Vigier, K.; Royer, S.; Jérôme, F. Deep eutectic solvents: Syntheses, properties and applications. Chem. Soc. Rev.; 2012; 41, pp. 7108-7146. [DOI: https://dx.doi.org/10.1039/c2cs35178a]

45. El Achkar, T.; Greige-Gerges, H.; Fourmentin, S. Basics and properties of deep eutectic solvents: A review. Environ. Chem. Lett.; 2021; 19, pp. 3397-3408. [DOI: https://dx.doi.org/10.1007/s10311-021-01225-8]

46. Brinkman, H.R.; Landi, J.J., Jr.; Paterson, J.B., Jr.; Stone, P.J. The Use of P-Toluenesulfonic Acid for Removal of the NT-Butoxy-Carbonyl Protecting Group in Solid Phase Peptide Synthesis. Synth. Commun.; 1991; 21, pp. 459-465. [DOI: https://dx.doi.org/10.1080/00397919108016770]

47. Kocienski, P.J. Protecting Groups; Georg Thieme: New York, NY, USA, 2004.

48. Di Gioia, M.L.; Gagliardi, A.; Leggio, A.; Leotta, V.; Romio, E.; Liguori, A. N-Urethane protection of amines and amino acids in an ionic liquid. RSC Adv.; 2015; 5, pp. 63407-63420. [DOI: https://dx.doi.org/10.1039/C5RA12121C]

49. Azizi, N.; Shirdel, F. Sustainable and chemoselective N-Boc protection of amines in biodegradable deep eutectic solvent. Monatsh. Chem.; 2017; 148, pp. 1069-1074. [DOI: https://dx.doi.org/10.1007/s00706-016-1856-x]

50. Jahani, F.; Tajbakhsh, M.; Khaksar, S.; Azizi, M.R. An efficient and highly chemoselective N-Boc protection of amines, amino acids, and peptides under heterogeneous conditions. Monatsh. Chem.; 2011; 142, pp. 1035-1043. [DOI: https://dx.doi.org/10.1007/s00706-011-0534-2]

51. Di Gioia, M.L.; Costanzo, P.; De Nino, A.; Maiuolo, L.; Nardi, M.; Olivito, F.; Procopio, A. Simple and efficient Fmoc removal in ionic liquid. RSC Adv.; 2017; 758, pp. 36482-36491. [DOI: https://dx.doi.org/10.1039/C7RA04425A]

52. Nardi, M.; Gioia, M.L.D.; Costanzo, P.; Nino, A.D.; Maiuolo, L.; Oliverio, M.; Olivito, F.; Procopio, A. Selective acetylation of small biomolecules and their derivatives catalyzed by Er(OTf)₃. Catalysts; 2017; 7, 269. [DOI: https://dx.doi.org/10.3390/catal7090269]

53. Cui, Y.; Li, C.; Bao, M. Deep eutectic solvents (DESs) as powerful and recyclable catalysts and solvents for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones. Green Proc. Synth.; 2019; 8, pp. 568-576. [DOI: https://dx.doi.org/10.1515/gps-2019-0026]

54. Adeeb Hayyan, A.; Hashim, M.A.; Hayyan, M.; Mjalli, F.S.; AlNashef, I.M. A new processing route for cleaner production of biodiesel fuel using a choline chloride based deep eutectic solvent. J. Clean. Prod.; 2014; 65, pp. 246-251. [DOI: https://dx.doi.org/10.1016/j.jclepro.2013.08.031]

55. Sheldon, R.A. Metrics of Green Chemistry and Sustainability: Past, Present, and Future. ACS Sustain. Chem. Eng.; 2018; 6, pp. 32-48. [DOI: https://dx.doi.org/10.1021/acssuschemeng.7b03505]

56. Monteith, E.R.; Mampuys, P.; Summerton, L.; Clark, J.H.; Maes, B.U.W.; McElroy, C.R. Why we might be misusing process mass intensity (PMI) and a methodology to apply it effectively as a discovery level metric. Green Chem.; 2020; 22, pp. 123-135. [DOI: https://dx.doi.org/10.1039/C9GC01537J]

57. Gawande, M.B.; Branco, P.S. An efficient and expeditious Fmoc protection of amines and amino acids in aqueous media. Green Chem.; 2011; 13, pp. 3355-3359. [DOI: https://dx.doi.org/10.1039/c1gc15868f]

58. Meneses, L.; Santos, F.; Gameiro, A.R.; Paiva, A.; Duarte, A.R.C. Preparation of binary and ternary deep eutectic systems. J. Vis. Exp.; 2019; 152, 60326. [DOI: https://dx.doi.org/10.3791/60326]

59. Qin, H.; Hu, X.; Wang, J.; Cheng, H.; Chen, L.; Qi, Z. Overview of acidic deep eutectic solvents on synthesis, properties and applications. Green Energy Environ.; 2020; 5, pp. 8-21. [DOI: https://dx.doi.org/10.1016/j.gee.2019.03.002]

60. Abbott, A.P.; Boothby, D.; Capper, G.; Davies, D.L.; Rasheed, R.K.J. Deep eutectic solvents formed between choline chloride and carboxylic acids: Versatile alternatives to ionic liquids. Am. Chem. Soc.; 2004; 9, 29. [DOI: https://dx.doi.org/10.1021/ja048266j]