Preparation of Thioaminals in Water

The presence of sulfur–carbon bonds is transversal to several areas of chemistry, e.g., drug discovery, materials, and chemical biology. However, a lack of efficient and sustainable procedures for the preparation of thioaminals, the N,S-analogues of O,O-acetals, contributes to this functional group often being overlooked by the scientific community. In this work is described the formation of thioaminals in water promoted by copper(II) triflate.


Introduction
The preparation of sulfur-rich frameworks has been a relevant topic for organic chemists, given its importance in materials [1-4] and medicinal chemistry [5,6]. The need for the formation of C-S bonds led to developments such as the click thio-ene reaction, a cornerstone of material chemistry [1]. Additionally, thio-Michael additions are often used for the derivatization of activated olefins, a strategy widely used for the functionalization of materials and peptides [6,7].
Recently, there has been an increased concern about the development of sustainable methodologies [24][25][26][27], including procedures in water [28][29][30][31][32]. With this in mind, our group (i) focused on the valorization of raw renewable materials such as furfural and hydroxymethylfurfural (HMF) [33][34][35] and (ii) reported on the use of water as a green reaction media for the production of cyclopentenones [36] and, more recently, aminals from the condensation of aryl aldehydes with amines [37]. This addresses one of the 12 principles of green chemistry [24], namely the use of less hazardous/toxic chemicals. The structural resemblance of aminals and thioaminals led us to enquire if a similar methodology could be applied to their formation. Herein is described the formation of thioaminals under aqueous conditions promoted by copper(II) triflate ( Figure 1C).   [20][21][22][23] this work (C).

Results
Selecting furfural, morpholine and thiophenol as model substrates, a screening of conditions was initially performed to identify the most suitable catalyst and solvent (Table 1). The formation of thioaminal 1 in the presence of catalytic copper(II) triflate (1 mol%) in aqueous media afforded the desired product in 84% isolated yield after 10 min of reaction (Table 1, entry 3). In the absence of catalyst, 100% of starting furfural was recovered (Table 1, entry 1), while an increase in catalyst loading to 10 mol% resulted in full conversion to the corresponding cyclopentenone (Table 1, entry 2) [36,38]. Other attempted metal-based catalysts (i.e., CuSO4, FeCl3, AlCl3 and ZnCl2) and Brønsted acids (i.e., triflic acid) also led to the formation of cyclopentenone as a side-product (Table 1,  [20][21][22][23] this work (C).

Results
Selecting furfural, morpholine and thiophenol as model substrates, a screening of conditions was initially performed to identify the most suitable catalyst and solvent (Table 1). The formation of thioaminal 1 in the presence of catalytic copper(II) triflate (1 mol%) in aqueous media afforded the desired product in 84% isolated yield after 10 min of reaction (Table 1, entry 3). In the absence of catalyst, 100% of starting furfural was recovered (Table 1, entry 1), while an increase in catalyst loading to 10 mol% resulted in full conversion to the corresponding cyclopentenone (Table 1, entry 2) [36,38]. Other attempted metal-based catalysts (i.e., CuSO 4 , FeCl 3 , AlCl 3 and ZnCl 2 ) and Brønsted acids (i.e., triflic acid) also led to the formation of cyclopentenone as a side-product (Table 1, entries 7-11) [36,38]. Performing the reaction under neat conditions or by changing the solvent to ethanol or acetonitrile did not allow full conversion and caused a visible contamination with cyclopentenone (Table 1, entries 4-6). Thus, water was considered the most suitable solvent for this reaction.  [36,38]. Performing the reaction under neat conditions or by changing the solvent to ethanol or acetonitrile did not allow full conversion and caused a visible contamination with cyclopentenone (Table 1, entries 4-6). Thus, water was considered the most suitable solvent for this reaction. CuSO4 (1 mol%) H2O 100 35 8 FeCl3 (1 mol%) H2O 100 0 9 AlCl3 (1 mol%) H2O 100 12 10 ZnCl2 (1 mol%) H2O 100 70 11 TfOH (2 mol%) H2O 87 40 Following the best selected conditions, we expanded the scope to a plethora of aryl and alkyl aldehydes (Scheme 1). First, we reacted benzaldehyde, morpholine and thiophenol to prepare thioaminal 2 in 76% yield. Electron-rich aromatic aldehydes, such as 4-NMe2-benzaldehyde and 4-OMe-benzaldehyde, resulted in no reaction or incomplete reaction (65% conversion), and were impossible to isolate due to the product instability. Similar results were obtained when alkyl aldehydes were employed, resulting in a complex mixture.
Counterintuitively, 4-Me-benzaldehyde afforded a better yield than 4-CF3benzaldehyde, and a similar yield was obtained for the 4-Br-benzaldehyde derivative. Being electron poor, the formation of 4 and 5 should be favored since the aldehyde is more prone to undergo condensation with the secondary amine. Moreover, the use of 4-NO2-benzaldehyde only gave a 50% conversion to the corresponding thioaminal, without the possibility of purification. These unexpected results led us to conclude that other factors such as the stability of the constructs may play a role when analyzing the success of these reactions.
To our surprise, we did not observe the formation of the N,N aminal product in this aldehyde scope, which clearly indicates that the N,S thioaminals are thermodynamically more favorable. However, if we allowed for the reaction to proceed for longer periods of time, the yields would drop significantly. In this situation, no aldehyde is observed as well, indicating another decomposition pathway than the simple hydrolysis of the thioaminal. Focusing on isolation, we stumbled upon a major challenge, which was the hydrolysis of the thioaminals. Simple operations such as extraction, even at higher pH using NaHCO3 (sat aq.), led to hydrolysis and subsequently low yields of the products. Freeze-drying the solution, followed by washing the corresponding powders with cold water, significantly increased the isolated yields. Contrary to other prepared thioaminals, product 1, obtained from furfural, exhibited increased stability even during the work-up extraction with MTBE. Following the best selected conditions, we expanded the scope to a plethora of aryl and alkyl aldehydes (Scheme 1). First, we reacted benzaldehyde, morpholine and thiophenol to prepare thioaminal 2 in 76% yield. Electron-rich aromatic aldehydes, such as 4-NMe 2benzaldehyde and 4-OMe-benzaldehyde, resulted in no reaction or incomplete reaction (65% conversion), and were impossible to isolate due to the product instability. Similar results were obtained when alkyl aldehydes were employed, resulting in a complex mixture. A search for secondary aliphatic and aromatic amines was also performed (Scheme 2). In addition to morpholine, other aliphatic amines such as piperidine, N-methyl piperazine and dibenzyl amine were tolerated under the reaction conditions, affording the corresponding thioaminals 6-8 in a good to excellent yield. These compounds exhibited hygroscopic properties, resulting in fast hydrolysis at room temperature or at 5 °C. Bulky aliphatic amines, such as di-isopropylamine, did not react and the reagents were Counterintuitively, 4-Me-benzaldehyde afforded a better yield than 4-CF 3 -benzaldehyde, and a similar yield was obtained for the 4-Br-benzaldehyde derivative. Being electron poor, the formation of 4 and 5 should be favored since the aldehyde is more prone to undergo condensation with the secondary amine. Moreover, the use of 4-NO 2 -benzaldehyde only gave a 50% conversion to the corresponding thioaminal, without the possibility of purification. These unexpected results led us to conclude that other factors such as the stability of the constructs may play a role when analyzing the success of these reactions.
To our surprise, we did not observe the formation of the N,N aminal product in this aldehyde scope, which clearly indicates that the N,S thioaminals are thermodynamically more favorable. However, if we allowed for the reaction to proceed for longer periods of time, the yields would drop significantly. In this situation, no aldehyde is observed as well, indicating another decomposition pathway than the simple hydrolysis of the thioaminal. Focusing on isolation, we stumbled upon a major challenge, which was the hydrolysis of the thioaminals. Simple operations such as extraction, even at higher pH using NaHCO 3 (sat aq.), led to hydrolysis and subsequently low yields of the products. Freeze-drying the solution, followed by washing the corresponding powders with cold water, significantly increased the isolated yields. Contrary to other prepared thioaminals, product 1, obtained from furfural, exhibited increased stability even during the work-up extraction with MTBE.
A search for secondary aliphatic and aromatic amines was also performed (Scheme 2). In addition to morpholine, other aliphatic amines such as piperidine, N-methyl piperazine and dibenzyl amine were tolerated under the reaction conditions, affording the corresponding thioaminals 6-8 in a good to excellent yield. These compounds exhibited hygroscopic properties, resulting in fast hydrolysis at room temperature or at 5 • C. Bulky aliphatic amines, such as di-isopropylamine, did not react and the reagents were fully recovered. Surprisingly, diethylamine was also not a successful amine. An aromatic amine, N-methyl aniline, was employed under the reaction conditions, but no reaction occurred. A search for secondary aliphatic and aromatic amines was also performed (Scheme 2). In addition to morpholine, other aliphatic amines such as piperidine, N-methyl piperazine and dibenzyl amine were tolerated under the reaction conditions, affording the corresponding thioaminals 6-8 in a good to excellent yield. These compounds exhibited hygroscopic properties, resulting in fast hydrolysis at room temperature or at 5 °C. Bulky aliphatic amines, such as di-isopropylamine, did not react and the reagents were fully recovered. Surprisingly, diethylamine was also not a successful amine. An aromatic amine, N-methyl aniline, was employed under the reaction conditions, but no reaction occurred. Scheme 2. Scope of alkyl amines for the formation of thioaminals.
Next, a series of aryl and aliphatic thiols were reacted with benzaldehyde and morpholine (Scheme 3). The reaction withstood electron-rich thiols such as 4-Me, 3,5-diMe, 4-OMe and 3,4-diOMe thiophenol yielding the thioaminal products 9-12 in good yield. Electron-poor thiol such as 4-F, 4-Cl and 3,5-diCl thiophenol also afforded the desired products, 13-15, in good to excellent yields. A reaction with 4-NO 2 -thiophenol was also attempted, but only 63% conversion to the thioaminal was observed, without the possibility of purification. Finally, alkyl thiols also afforded products 16-19 in good yield, even when long-alkyl-chain thiols (i.e., dodecanethiol) were employed. attempted, but only 63% conversion to the thioaminal was observed, without the possibility of purification. Finally, alkyl thiols also afforded products 16-19 in good yield, even when long-alkyl-chain thiols (i.e., dodecanethiol) were employed. Scheme 3. Scope of aryl and alkyl thiols for the formation of thioaminals.
An additional reaction using three solid substrates (i.e., 4-Br-benzaldehyde, 4-Clthiophenol and N-acetylated piperazine) was performed in water. The corresponding thiominal was formed to some extent (68% conversion), indicating that solid substrates are more challenging and that the use of organic solvents might be necessary.
Intrigued by the selective formation of the thioaminal, a solution of the aminal in acetonitrile was reacted with thiophenol in the presence of a catalyst and a full conversion of aminal 20 was observed to the corresponding thioaminal 2, isolated in 94% yield (Scheme 4). The proposed mechanism for the formation of the thioaminals depicted in Figure 2 is initiated by the formation of an iminium ion, which may either undergo further con-Scheme 3. Scope of aryl and alkyl thiols for the formation of thioaminals.
An additional reaction using three solid substrates (i.e., 4-Br-benzaldehyde, 4-Clthiophenol and N-acetylated piperazine) was performed in water. The corresponding thiominal was formed to some extent (68% conversion), indicating that solid substrates are more challenging and that the use of organic solvents might be necessary.
Intrigued by the selective formation of the thioaminal, a solution of the aminal in acetonitrile was reacted with thiophenol in the presence of a catalyst and a full conversion of aminal 20 was observed to the corresponding thioaminal 2, isolated in 94% yield (Scheme 4). attempted, but only 63% conversion to the thioaminal was observed, without the possibility of purification. Finally, alkyl thiols also afforded products 16-19 in good yield, even when long-alkyl-chain thiols (i.e., dodecanethiol) were employed. Scheme 3. Scope of aryl and alkyl thiols for the formation of thioaminals.
An additional reaction using three solid substrates (i.e., 4-Br-benzaldehyde, 4-Clthiophenol and N-acetylated piperazine) was performed in water. The corresponding thiominal was formed to some extent (68% conversion), indicating that solid substrates are more challenging and that the use of organic solvents might be necessary.
Intrigued by the selective formation of the thioaminal, a solution of the aminal in acetonitrile was reacted with thiophenol in the presence of a catalyst and a full conversion of aminal 20 was observed to the corresponding thioaminal 2, isolated in 94% yield (Scheme 4). The proposed mechanism for the formation of the thioaminals depicted in Figure 2 is initiated by the formation of an iminium ion, which may either undergo further con- The proposed mechanism for the formation of the thioaminals depicted in Figure 2 is initiated by the formation of an iminium ion, which may either undergo further condensation with an amine (path a) or with a thiol (path b) to form the desired product. The fact that aminals in the presence of thiol lead to the formation of thioaminals suggests that even when the aminal is formed, its reversibility by the elimination of an amine generates the parent iminium ion, which will react with the thiol to form the product thioaminal. densation with an amine (path a) or with a thiol (path b) to form the desired product. The fact that aminals in the presence of thiol lead to the formation of thioaminals suggests that even when the aminal is formed, its reversibility by the elimination of an amine generates the parent iminium ion, which will react with the thiol to form the product thioaminal. Following our previous studies on the stability of N,N-aminals, in which was observed that the electron-donating groups in the aldehyde stabilized the products, we enquired into the role of substituents in the arylthiol. To this end, we accessed the rates of hydrolysis of three thioaminals bearing electron-withdrawing (14) and electrondonating (9,11) para substituents by UV-vis spectroscopy, as depicted in Figure 3. We observed a fast hydrolysis of <20 s in these diluted conditions (see Supplementary Materials, Figures S21-S23). Despite this, a trend was observed where electron-withdrawing substituents on the thiol slightly hindered the hydrolysis of the products.  Following our previous studies on the stability of N,N-aminals, in which was observed that the electron-donating groups in the aldehyde stabilized the products, we enquired into the role of substituents in the arylthiol. To this end, we accessed the rates of hydrolysis of three thioaminals bearing electron-withdrawing (14) and electron-donating (9,11) para substituents by UV-vis spectroscopy, as depicted in Figure 3. We observed a fast hydrolysis of <20 s in these diluted conditions (see Supplementary Materials, Figures S21 and S23). Despite this, a trend was observed where electron-withdrawing substituents on the thiol slightly hindered the hydrolysis of the products. densation with an amine (path a) or with a thiol (path b) to form the desired product. The fact that aminals in the presence of thiol lead to the formation of thioaminals suggests that even when the aminal is formed, its reversibility by the elimination of an amine generates the parent iminium ion, which will react with the thiol to form the product thioaminal. Following our previous studies on the stability of N,N-aminals, in which was observed that the electron-donating groups in the aldehyde stabilized the products, we enquired into the role of substituents in the arylthiol. To this end, we accessed the rates of hydrolysis of three thioaminals bearing electron-withdrawing (14) and electrondonating (9,11) para substituents by UV-vis spectroscopy, as depicted in Figure 3. We observed a fast hydrolysis of <20 s in these diluted conditions (see Supplementary Materials, Figures S21-S23). Despite this, a trend was observed where electron-withdrawing substituents on the thiol slightly hindered the hydrolysis of the products.

General Information
All solvents were of analytical grade and distilled prior to use. All reagents were used as received from commercial suppliers. NMR spectra were recorded in a Bruker Fourier 300 or Bruker Advance 400 spectrometer. High-Resolution Mass Spectrometry (HRMS) results were recorded in a Thermo Scientific Q Exactive hybrid quadrupole-Orbitrap mass spectrometer (Thermo Scientific TM Q Exactive TM Plus, Waltham, Massachusetts, U.S.). 1 H NMR, 13

General Procedure for Cu(II)-Catalyzed Preparation of Thioaminals in Water
Aldehyde (0.942 mmol, 1 equiv) and morpholine (0.942 mmol, 1 equiv) were placed in a round-bottom flask followed by addition of aqueous stock solution of Cu(OTf) 2 (1 mol%, 227 µL from 15 mg/mL stock solution). Then, thiol (0.942 mmol, 1 equiv) was added. The reaction was stirred at room temperature for 10 min and water removed by lyophilization to obtain pure thioaminals. Additional purification might have been required by washing with distilled water (pH 9-10). In the case of thioaminal 1, an extraction with MTBE was performed.

General Procedure for the Thiol Exchange
Aminal 20 (0.100 g, 0.381 mmol) was dissolved in a freshly prepared solution of Cu(OTf) 2 (0.00138 g, 0.01 equiv) in acetonitrile (1.9 mL). Thiophenol (0.042 g, 0.381 mmol) was added and the mixture was allowed to react for 10 min. The crude was evaporated under reduced pressure and the obtained solid was washed with cold distilled water (5 mL), yielding thioaminal 2 as a pale-yellow solid (0.102 g, 94% yield).

General Procedure for UV Stabilities Experiments of Thioaminals 9, 11 and 14
Thioaminals were dissolved in MeOH (10 mM) and diluted in a solution of MeCN or ammonium acetate 20 mM (pH 7) buffer at 0.01 mM.
Then, 10 mM solutions of aminals 9, 11 and 14 in methanol were freshly prepared and were diluted in 2 mL of acetonitrile or ammonium acetate 20 mM (pH 7) buffer to a final concentration of 100 µM. The quartz cuvette was swiftly mixed by inversion and analyzed by UV-Visible spectroscopy. Full-scan analyses were performed every minute until a constant absorbance value was reached. To compare the results obtained, we plotted the absorbance values obtained for each thioaminal at a particular wavelength over time (250 nm).

Conclusions
The preparation of N,S-thioaminals is an ongoing challenge, due to both the reactivity and the stability of the products. Previous conditions required high temperatures and/or hazardous reagents. In accordance with the principles of green chemistry, in this work we expanded our previously reported conditions to thioaminals, affording the products under mild conditions, in aqueous media promoted by catalytic amounts of base metal copper(II) triflate. We hope that this report will contribute to the valorization of the thioaminal scaffold, both for drug discovery but also as a synthon for further derivatizations.
Supplementary Materials: The following supporting information can be downloaded online. Figures S1-S20: 1 H NMR, 13 C NMR of compounds 1-19. Figure S21: Variation of UV spectrum of thioaminal 9 after 20 s at pH 7; Figure S22: Variation of UV spectrum of thioaminal 11 after 20 s at pH 7; Figure S23: Variation of UV spectrum of thioaminal 14 after 20 s at pH 7. Reference [41] is Cited in Supplementary Materials. Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.
Data Availability Statement: Electronic supplementary information is given, including all NMR spectra and additional experimental details regarding UV stabilities studies.