1. 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
2SO
4, but under severe conditions (temperature above 140 °C) [
9].
Various other formylating agents have been reported, including chloral [
10], acetic formic anhydride [
11], formic acid [
12], ammonium formate [
13], formate esters [
14], polymer-supported formate [
15], ethyl formate [
16], triethyl orthoformate [
1,
2], aldehydes and methanol [
17], carbon monoxide [
18], and carbon dioxide [
19]. However, these also tend to suffer from similar problems of long reaction times (hours to days), variable or low yields, and harsh conditions (or expensive catalyst systems).
Several catalysts have been employed for the formylation of amines, including silica-supported sulfuric acid [
20], H
2SO
4/NaHSO
4-activated charcoal [
21], K-F alumina [
22], Amberlite IR 120 [
23], ZnO [
24], nano-CeO
2 [
25], nano-MgO [
26], natrolite zeolite [
27], indium metal [
28], sulfated titania [
29], and sulfated tungstate [
30], among others (
Table 1).
In the absence of a catalyst or promoter,
N-formylation of amines is a sluggish reaction that usually requires unique reaction conditions or long time frames for completion [
25]. However, some of these methods have quite a number of limitations, including harsh reaction conditions, the need for expensive metal catalysts or organocatalysts, and long reaction time frames. Thus, for organic transformations, the development of a safe, benign, environmentally friendly, high-yield, quick-reaction, and recyclable catalyst for
N-formylation of amines remains extremely desirable [
3].
In the last few years, H
2SO
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
2SO
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
2SO
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
2SO
4–SiO
2-catalyzed formylation with triethyl orthoformate have been published, and so for the first time, we present findings in this regard.
2. 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).
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
2SO
4–SiO
2 was not beneficial for faster conversion. Conversely, a lower amount of H
2SO
4–SiO
2 led to substantially slower conversion. The background reaction (used as a model) was also measured in the absence of H
2SO
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).
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).
3. 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
2SO
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
2SO
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, 1H NMR, and 13C 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
1H and
13C 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].
4. 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 CDCl3 or DMSO-d6 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).
4.1. Preparation of Sulfuric Acid Adsorbed on Silica Gel (H2SO4–SiO2)
The preparation of H
2SO
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
2SO
4 (1.5 g, 15.5 mmol, 0.8 mL of a 98% aq. solution of H
2SO
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
2SO
4–SiO
2 as a free-flowing powder.
4.2. A General Procedure for N-Formylation of Amines with Triethyl Orthoformate Promoted by Immobilized H2SO4 on Silica Gel
To a mixture of aniline (0.548 mL, 6 mmol) and triethyl orthoformate (24 mmol), the immobilized H2SO4 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 Na2SO4 and concentrated. The residue was subjected to column chromatography and eluted with (EtOAc–Pet Ether (3:1)) to afford the product in high yields.
5. 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 H2SO4–SiO2 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.