Catalytic Performance of Immobilized Sulfuric Acid on Silica Gel for N-Formylation of Amines with Triethyl Orthoformate

In the search for convenient, green, and practical catalytic methods for the current interest in organic synthesis, a simple, green, and highly efficient protocol for N-formylation of various amines was carried out in the presence of immobilized sulfuric acid on silica gel (H2SO4–SiO2). All reactions were performed in refluxing triethyl orthoformate (65 °C). The product formamides were obtained with high-to-excellent yields within 4 min to 2 h. The current approach is advantageous, due to its short reaction time and high yields. The catalyst is recyclable with no significant loss in catalytic efficiency.


Introduction
A fascinating trend in the synthesis of widely used organic molecules is the focus on green chemistry, including efficient reactions and the use of ecologically friendly reagents [1]. The use of silica gel as an effective catalyst in chemical processes has attracted much attention in recent years. The formylation of amines is a crucial process in organic chemistry, owing to the widespread application of N-formyl amine derivatives in industry and in biologically active compounds, such as fluoroquinolones, substituted imidazoles, 1,2-dihydroquinolines, and nitrogen-bridged heterocycles, among others [2]. N-formyl amine derivatives have also been used as reagents in Vilsmeier formylation reactions as amino acid-protecting groups [3] and in the synthesis of several other important derivatives, such as formamidines [4], isocyanates [5], and nitriles [6] (Figure 1).
Despite the fact that there are a variety of reagents for N-formylation of amines, the synthesis of formamides utilizing triethyl orthoformate as a formylating agent is still popular [1]. The reaction of ethyl orthoformate with aniline to afford N,N -diphenylformamidine was initially reported in 1869 by Wichelhaus [7]. Subsequently, Claisen synthesized ethyl N-phenylformimidate in low yields from the same reactants, but under slightly different experimental conditions [8]. Swaringen and colleagues went on to show that the reaction of N-alkylanilines with orthoformates in the absence of a catalyst or with hydrochloric/acetic acid produced orthoamides in low yields [8]. These few examples demonstrate one of the major drawbacks of this system, namely, the low yield. Meanwhile, when p-toluenesulfonic acid was employed as a catalyst, high yields of N-alkylformanilides and N,N-dialkylanilines were generated, but the reactions still often required high temperatures and prolonged reaction times. For example, Swaringen and co-workers demonstrated the synthesis of N-ethyl formamides from the reaction of amines with triethyl orthoformate in the presence of H 2 SO 4 , but under severe conditions (temperature above 140 • C) [9]. Despite the fact that there are a variety of reagents for N-formylation of amines, the synthesis of formamides utilizing triethyl orthoformate as a formylating agent is still popular [1]. The reaction of ethyl orthoformate with aniline to afford N,N'-diphenylformamidine was initially reported in 1869 by Wichelhaus [7]. Subsequently, Claisen synthesized ethyl N-phenylformimidate in low yields from the same reactants, but under slightly different experimental conditions [8]. Swaringen and colleagues went on to show that the reaction of N-alkylanilines with orthoformates in the absence of a catalyst or with hydrochloric/acetic acid produced orthoamides in low yields [8]. These few examples demonstrate one of the major drawbacks of this system, namely, the low yield. Meanwhile, when p-toluenesulfonic acid was employed as a catalyst, high yields of N-alkylformanilides and N,N-dialkylanilines were generated, but the reactions still often required high temperatures and prolonged reaction times. For example, Swaringen and co-workers demonstrated the synthesis of N-ethyl formamides from the reaction of amines with triethyl orthoformate in the presence of H2SO4, but under severe conditions (temperature above 140 °C) [9].
In the last few years, H 2 SO 4 -SiO 2 (Table 2) has demonstrated significant promise as a cost-effective and easily retrievable solid catalyst for driving a variety of essential organic reactions in solvent-free environments. H 2 SO 4 -SiO 2 is appealing for industrial usage because of its high catalytic activity, operational simplicity, and recyclability. There are two types of functional groups on the silica surface: siloxane (Si-O-Si) and silanol (Si-OH). Thus, silica gel modification can occur through the reaction of a specific molecule with either the siloxane (nucleophilic substitution at the Si) or silanol (direct reaction with the hydroxyl group) functions, though it is widely accepted that the reaction with the silanol function is the most common modification pathway ( Figure 2) [47,48]. The notion of employing H 2 SO 4 -SiO 2 as a transamidation catalyst was inspired by Rasheed et al. [20]. We became interested in employing the same catalyst to build a generic formylation with triethyl orthoformate. To the best of our knowledge, no reports of H 2 SO 4 -SiO 2 -catalyzed formylation with triethyl orthoformate have been published, and so for the first time, we present findings in this regard.

Results and Discussion
Initially, the reaction of aniline with triethyl orthoformate was chosen reaction (Figure 3). During the optimization of reaction parameters, it was aniline reacted smoothly with triethyl orthoformate, providing the desired a good yield (96%) within a short period of time (Table 3). In order to generalize the protocol for the formylation of sterically hin the reaction was optimized with respect to temperature and molar ratio. Th was raised to 65 °C and was observed to be quite sufficient to carry out the an optimum yield of the desired product (Table 3). It was observed that th excess of triethyl orthoformate was no longer required, as a 1:3 molar rati triethyl orthoformate was sufficient to yield the desired product (Table 3, en   Table 3. Optimization of reaction parameters for N-formylation of amines with tr mate (TEOF).

Results and Discussion
Initially, the reaction of aniline with triethyl orthoformate was chosen as the model reaction ( Figure 3). During the optimization of reaction parameters, it was observed that aniline reacted smoothly with triethyl orthoformate, providing the desired product with a good yield (96%) within a short period of time (Table 3).

Results and Discussion
Initially, the reaction of aniline with triethyl orthoformate was chosen reaction (Figure 3). During the optimization of reaction parameters, it was aniline reacted smoothly with triethyl orthoformate, providing the desired a good yield (96%) within a short period of time (Table 3). In order to generalize the protocol for the formylation of sterically hin the reaction was optimized with respect to temperature and molar ratio. Th was raised to 65 °C and was observed to be quite sufficient to carry out the an optimum yield of the desired product (Table 3). It was observed that th excess of triethyl orthoformate was no longer required, as a 1:3 molar rat triethyl orthoformate was sufficient to yield the desired product (Table 3, e   Table 3. Optimization of reaction parameters for N-formylation of amines with tr mate (TEOF).

Entry
Reaction Condition Time 1 Aniline (1 mmol)/TEOF (1 mmol), SIS (0.2 g) 10 min 2 Aniline (1 mmol)/TEOF (2 mmol), SIS (0.2 g) 6 min  In order to generalize the protocol for the formylation of sterically hindered amines, the reaction was optimized with respect to temperature and molar ratio. The temperature was raised to 65 • C and was observed to be quite sufficient to carry out the reaction with an optimum yield of the desired product (Table 3). It was observed that the need for an excess of triethyl orthoformate was no longer required, as a 1:3 molar ratio of amine to triethyl orthoformate was sufficient to yield the desired product (Table 3, entry 3).
We next explored the impact of immobilized sulfuric acid on silica gel stoichiometry on the outcome of the reaction (Table 4). We observed that excess H 2 SO 4 -SiO 2 was not beneficial for faster conversion. Conversely, a lower amount of H 2 SO 4 -SiO 2 led to substantially slower conversion. The background reaction (used as a model) was also measured in the absence of H 2 SO 4 -SiO 2 , confirming its vital role. In general, the reaction proceeded efficiently, with various amines reacting with triethyl orthoformate to produce the corresponding N-formylated product with good-to-excellent yield within a very short time. Aliphatic and aromatic primary amines underwent smooth N-formylation and gave the product in 70-96% yields (Table 5). Table 5. N-formylation of amines using triethyl orthoformate in the presence of immobilized sulfuric acid on silica gel.

Entry
Amines Time (Min) Product Yield (%) 1 reaction conditions, various functional groups were tolerated. However, eral method for generating amide bonds will surely benefit the drug disc In general, the formylation of aryl/heteroaryl amines (electron-neutral, -ri aliphatic, and cyclic secondary amines afforded the formylation produc yields (70-96%). Interestingly, sterically hindered aryl amines, such as pro 11, 16, 17, and 33-38, were found to react smoothly under the optimized r tions, demonstrating good yields of desired products. Less reactive het such as 42-51 and 56, produced the product with a surprisingly high yield a longer reaction time (35-60 min). When secondary amines 52-54 were reaction was somehow slow, providing a good yield of products in 1 h ( spectral data of all synthesized compounds are available in the Supplemen (S1-S56). reaction conditions, various functional groups were tolerated. However, finding a eral method for generating amide bonds will surely benefit the drug discovery pro In general, the formylation of aryl/heteroaryl amines (electron-neutral, -rich, -defici aliphatic, and cyclic secondary amines afforded the formylation products in exce yields (70-96%). Interestingly, sterically hindered aryl amines, such as products 6, 7 11, 16, 17, and 33-38, were found to react smoothly under the optimized reaction co tions, demonstrating good yields of desired products. Less reactive hetero aroma such as 42-51 and 56, produced the product with a surprisingly high yield (77-90%) a longer reaction time (35-60 min). When secondary amines 52-54 were employed reaction was somehow slow, providing a good yield of products in 1 h (Table 5). N spectral data of all synthesized compounds are available in the Supplementary Mate (S1-S56). demonstrate good yields of desired products (85-96%). Generally, under th reaction conditions, various functional groups were tolerated. However, eral method for generating amide bonds will surely benefit the drug disc In general, the formylation of aryl/heteroaryl amines (electron-neutral, -ri aliphatic, and cyclic secondary amines afforded the formylation produc yields (70-96%). Interestingly, sterically hindered aryl amines, such as pro 11, 16, 17, and 33-38, were found to react smoothly under the optimized r tions, demonstrating good yields of desired products. Less reactive het such as 42-51 and 56, produced the product with a surprisingly high yield a longer reaction time (35-60 min). When secondary amines 52-54 were reaction was somehow slow, providing a good yield of products in 1 h (T spectral data of all synthesized compounds are available in the Supplemen (S1-S56). Table 5. N-formylation of amines using triethyl orthoformate in the presence of im furic acid on silica gel.

Entry
Amines demonstrate good yields of desired products (85-96%). Generally, under these optim reaction conditions, various functional groups were tolerated. However, finding a eral method for generating amide bonds will surely benefit the drug discovery pro In general, the formylation of aryl/heteroaryl amines (electron-neutral, -rich, -defici aliphatic, and cyclic secondary amines afforded the formylation products in exce yields (70-96%). Interestingly, sterically hindered aryl amines, such as products 6, 7 11, 16, 17, and 33-38, were found to react smoothly under the optimized reaction co tions, demonstrating good yields of desired products. Less reactive hetero aroma such as 42-51 and 56, produced the product with a surprisingly high yield (77-90%) a longer reaction time (35-60 min). When secondary amines 52-54 were employed reaction was somehow slow, providing a good yield of products in 1 h (Table 5). N spectral data of all synthesized compounds are available in the Supplementary Mate (S1-S56).

Reusability of Catalyst
The reusability of the catalytic system was explored. The catalyst wa simple filtration and washed with ethyl acetate after the reaction was com was reused for two consecutive cycles within the same time frame (4 min decrease in catalytic activity (9-13%) ( Table 6). Table 6. Efficiency of the recycled SIS in the N-formylation of aniline.

Entry
Turn Yield  1  1  96  2  2  89  3 3 83 In order to demonstrate the efficiency and versatility of the H2SO4-S compared the result of N-formylation of aniline with other protocols th published based on reaction times and yields ( Table 7). The results showed approaches required longer reaction times for efficient conversion than f protocol. Therefore, on this basis, the present protocol is more efficient o with other methodologies. Even though we have yet to prove the mechanism of our reaction in an manner, Figure 4 suggests a possible explanation. The first step is the ac electrophilic carbon of triethyl orthoformate by the sulfonic group of H2SO led to the formation of a cationic intermediate. The cationic intermediat amine nucleophiles, which, on further elimination of ethanol, furnishe formylated product.

Reusability of Catalyst
The reusability of the catalytic system was explored. The catalyst was separate simple filtration and washed with ethyl acetate after the reaction was completed, an was reused for two consecutive cycles within the same time frame (4 min), with a s decrease in catalytic activity (9-13%) ( Table 6). In order to demonstrate the efficiency and versatility of the H2SO4-SiO2 system compared the result of N-formylation of aniline with other protocols that have b published based on reaction times and yields ( Table 7). The results showed that the o approaches required longer reaction times for efficient conversion than for the pre protocol. Therefore, on this basis, the present protocol is more efficient or compar with other methodologies. Even though we have yet to prove the mechanism of our reaction in an experime manner, Figure 4 suggests a possible explanation. The first step is the activation o electrophilic carbon of triethyl orthoformate by the sulfonic group of H2SO4-SiO2, w led to the formation of a cationic intermediate.

Reusability of Catalyst
The reusability of the catalytic system was explored. The catalyst wa simple filtration and washed with ethyl acetate after the reaction was com was reused for two consecutive cycles within the same time frame (4 min decrease in catalytic activity (9-13%) ( Table 6). Table 6. Efficiency of the recycled SIS in the N-formylation of aniline.

Entry
Turn Yield  1  1  96  2  2  89  3 3 83 In order to demonstrate the efficiency and versatility of the H2SO4-S compared the result of N-formylation of aniline with other protocols t published based on reaction times and yields ( Table 7). The results showed approaches required longer reaction times for efficient conversion than f protocol. Therefore, on this basis, the present protocol is more efficient with other methodologies. Even though we have yet to prove the mechanism of our reaction in an manner, Figure 4 suggests a possible explanation. The first step is the ac electrophilic carbon of triethyl orthoformate by the sulfonic group of H2SO led to the formation of a cationic intermediate. The cationic intermediat amine nucleophiles, which, on further elimination of ethanol, furnishe formylated product.

Reusability of Catalyst
The reusability of the catalytic system was explored. The catalyst was separate simple filtration and washed with ethyl acetate after the reaction was completed, an was reused for two consecutive cycles within the same time frame (4 min), with a s decrease in catalytic activity (9-13%) ( Table 6). In order to demonstrate the efficiency and versatility of the H2SO4-SiO2 system compared the result of N-formylation of aniline with other protocols that have b published based on reaction times and yields ( Table 7). The results showed that the o approaches required longer reaction times for efficient conversion than for the pre protocol. Therefore, on this basis, the present protocol is more efficient or compar with other methodologies. Even though we have yet to prove the mechanism of our reaction in an experime manner, Figure 4 suggests a possible explanation. The first step is the activation of electrophilic carbon of triethyl orthoformate by the sulfonic group of H2SO4-SiO2, w led to the formation of a cationic intermediate. The cationic intermediate reacted amine nucleophiles, which, on further elimination of ethanol, furnished the des formylated product.

93
Aniline with electron-donating groups provided an excellent yield of 65-96% with triethyl orthoformate. The halogen (F, Cl, Br, I)-containing anilines provided good yields, ranging from 73% to 96%, of corresponding products. Similarly, electron-withdrawing groups were found to react smoothly under the optimized reaction conditions and demonstrate good yields of desired products (85-96%). Generally, under these optimized reaction conditions, various functional groups were tolerated. However, finding a general method for generating amide bonds will surely benefit the drug discovery process. In general, the formylation of aryl/heteroaryl amines (electron-neutral, -rich, -deficient), aliphatic, and cyclic secondary amines afforded the formylation products in excellent yields (70-96%). Interestingly, sterically hindered aryl amines, such as products 6, 7, 10, 11, 16, 17, and 33-38, were found to react smoothly under the optimized reaction conditions, demonstrating good yields of desired products. Less reactive hetero aromatics, such as 42-51 and 56, produced the product with a surprisingly high yield (77-90%) and a longer reaction time (35-60 min). When secondary amines 52-54 were employed, the reaction was somehow slow, providing a good yield of products in 1 h (Table 5). NMR spectral data of all synthesized compounds are available in the Supplementary Materials (S1-S56).

Reusability of Catalyst
The reusability of the catalytic system was explored. The catalyst was separated by simple filtration and washed with ethyl acetate after the reaction was completed, and it was reused for two consecutive cycles within the same time frame (4 min), with a slight decrease in catalytic activity (9-13%) ( Table 6). In order to demonstrate the efficiency and versatility of the H 2 SO 4 -SiO 2 system, we compared the result of N-formylation of aniline with other protocols that have been published based on reaction times and yields ( Table 7). The results showed that the other approaches required longer reaction times for efficient conversion than for the present protocol. Therefore, on this basis, the present protocol is more efficient or comparable with other methodologies.
Even though we have yet to prove the mechanism of our reaction in an experimental manner, Figure 4 suggests a possible explanation. The first step is the activation of the electrophilic carbon of triethyl orthoformate by the sulfonic group of H 2 SO 4 -SiO 2 , which led to the formation of a cationic intermediate. The cationic intermediate reacted with amine nucleophiles, which, on further elimination of ethanol, furnished the desired formylated product.  While 1,8-difformamido-naphthalein (38) and 3-formamido-1,2,4-triazole-5-thiol (53) are new derivatives and were characterized by one-and two-dimensional NMR analysis and high-resolution mass spectroscopy, all other products are known compounds and were identified by melting point, IR, 1 H NMR, and 13 C NMR spectroscopy. The synthesis of formamides was confirmed by IR spectra, which revealed two distinct absorption bands between 3300 and 3400 cm −1 (secondary NH) and 1640 and 1680 cm −1 (N-formyl, C=O).
Furthermore, formamide molecules have both a conformational stereogenic axis and a configurational stereogenic centre. These molecules take on two distinct syn and anti-conformational diastereomers as a result of restricted rotation around the Ar-N bond [50]. The 1 H and 13 C NMR spectra of most of the synthesized formamides at 25 °C were consistent with the presence of two rotamers. Only one rotamer was observed for the compounds 8, 14, 27, 45 and 46.
During the purification of compounds 12 and 35, two products appeared as partially separated spots on thin-layer chromatography (TLC) plates. Using normal silica gel chromatography, these compounds were identified as A and B rotamer pairs. After purifying compounds 12 and 35, pure rotamers 12A and 35A were isolated ( Figure 5). 12A and 35A were the only pure isomers that could be isolated, while 12B and 35B were always contaminated to some degree by 12A and 35A, respectively. The fact that we were able to isolate rotamers A and B at room temperature and characterize them using basic spectroscopic techniques astounded us. This occurrence may be viewed as a specific form of atropisomerism, because atropisomers are stereoisomers with restricted rotation around a single bond where the rotational barrier is high enough to allow isolation of the isomeric species [51]. While 1,8-difformamido-naphthalein (38) and 3-formamido-1,2,4-triazole-5-thiol (53) are new derivatives and were characterized by one-and two-dimensional NMR analysis and high-resolution mass spectroscopy, all other products are known compounds and were identified by melting point, IR, 1 H NMR, and 13 C NMR spectroscopy. The synthesis of formamides was confirmed by IR spectra, which revealed two distinct absorption bands between 3300 and 3400 cm −1 (secondary NH) and 1640 and 1680 cm −1 (N-formyl, C=O).
Furthermore, formamide molecules have both a conformational stereogenic axis and a configurational stereogenic centre. These molecules take on two distinct syn and anticonformational diastereomers as a result of restricted rotation around the Ar-N bond [50]. The 1 H and 13 C NMR spectra of most of the synthesized formamides at 25 • C were consistent with the presence of two rotamers. Only one rotamer was observed for the compounds 8, 14, 27, 45 and 46.
During the purification of compounds 12 and 35, two products appeared as partially separated spots on thin-layer chromatography (TLC) plates. Using normal silica gel chromatography, these compounds were identified as A and B rotamer pairs. After purifying compounds 12 and 35, pure rotamers 12A and 35A were isolated ( Figure 5). 12A and 35A were the only pure isomers that could be isolated, while 12B and 35B were always contaminated to some degree by 12A and 35A, respectively. The fact that we were able to isolate rotamers A and B at room temperature and characterize them using basic spectroscopic techniques astounded us. This occurrence may be viewed as a specific form of atropisomerism, because atropisomers are stereoisomers with restricted rotation around a single bond where the rotational barrier is high enough to allow isolation of the isomeric species [51]. able to isolate rotamers A and B at room temperature and characterize the spectroscopic techniques astounded us. This occurrence may be viewed as a of atropisomerism, because atropisomers are stereoisomers with restr around a single bond where the rotational barrier is high enough to allow i isomeric species [51].

Materials and Methods
A PerkinElmer Spectrum 100 FT-IR Spectrometer (Valencia, CA, USA) was used for the FT-IR analysis. The IR spectra were obtained by the attenuated total reflection (ATR) method. For each experiment, 16 scans were performed in the frequency range from 650 to 4000 cm −1 . Melting points of all the compounds were determined using a Koffler hot-stage apparatus and were uncorrected. NMR spectra were recorded on a Bruker Advance III 400 spectrometer (Rheinstetten, Germany) using CDCl 3 or DMSO-d 6 as a solvent with tetramethyl silane used as internal standard. LC-MS/MS data were recorded on a Bruker Compact quadrupole time of flight (QToF) mass spectrometer (Bremen, Germany). Raw mass spectrometry data were processed using MZmine software (version 2.38) (San Diego, CA, USA). Solvents and chemicals used were of analytical grade, purchased from Sigma Aldrich (St. Louis, MO, USA) and used without further purification. The purity determination of the starting materials and reaction monitoring were performed by thin-layer chromatography (TLC) on Merck silica gel G F254plates (Duren, Germany).

Preparation of Sulfuric Acid Adsorbed on Silica Gel (H 2 SO 4 -SiO 2 )
The preparation of H 2 SO 4 -SiO 2 was carried out by following the reported procedure [52]. To a suspension of silica gel (29.5 g, 230-400 mesh size) in EtOAc (60 mL), H 2 SO 4 (1.5 g, 15.5 mmol, 0.8 mL of a 98% aq. solution of H 2 SO 4 ) was added and the mixture was stirred magnetically for 30 min at room temperature. EtOAc was removed under reduced pressure (rotary evaporator) and the residue was heated at 100 • C for 72 h under vacuum to afford H 2 SO 4 -SiO 2 as a free-flowing powder.

A General Procedure for N-Formylation of Amines with Triethyl Orthoformate Promoted by Immobilized H 2 SO 4 on Silica Gel
To a mixture of aniline (0.548 mL, 6 mmol) and triethyl orthoformate (24 mmol), the immobilized H 2 SO 4 on silica gel (1.2 g) was then added and the reaction mixture was stirred under reflux conditions (65 • C). Progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with EtOAc (20 mL), filtered, water (30 mL) was added, the solution was extracted with EtOAc, and the combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated. The residue was subjected to column chromatography and eluted with (EtOAc-Pet Ether (3:1)) to afford the product in high yields.

Conclusions
We have developed a simple, green, and highly efficient protocol for N-formylation of various amines in the presence of immobilized sulfuric acid on silica gel, with excellent yields and remarkably simple and environmentally benign processes. The approach is compatible with a wide range of aromatic, heteroaromatic, aliphatic, and cyclic/acyclic primary or secondary amines. The H 2 SO 4 -SiO 2 catalytic system described here is a good complement to previously reported protocols, due to its ease of manipulation, low cost, and benign nature. We are optimistic that, with this approach, we will be able to develop the biologically relevant heterocyclic ring system more efficiently. This protocol is generic, and it will undoubtedly offer value to the growing area of organic synthesis.