Simple methods for the synthesis of N-substituted acryl amides using Na2CO3/SiO2 or NaHSO4/SiO2

Abstract A simple and efficient procedure for the synthesis of N-substituted acryl amides has been developed using Na2CO3/SiO2 or NaHSO4/SiO2. Na2CO3/SiO2 smoothly acts as a base in the reaction between acryloyl chloride and a variety of amines to obtain their corresponding products in good to excellent yield. Additionally, NaHSO4/SiO2 catalyzed the Ritter reaction between acryl nitrile and sec-benzylic alcohols to give the expected N-substituted acryl amide product. In both reactions, Na2CO3/SiO2 and NaHSO4/SiO2 were removed from the reaction mixture using filtration. GRAPHICAL ABSTRACT


Introduction
Acrylamide is widely used as an intermediate in organic synthesis. The demand for acrylamide is estimated at >200,000 t/y. Acrylamide was synthesized by Moureu in 1893 using ammonia and acryloyl chloride. [1] Subsequently, various methods have been developed to synthesize acrylamide, [2] but for economic reasons, the hydration reaction of acrylonitrile is adopted for the synthesis of acrylamide on an industrial scale. [3] In addition, polyacrylamide, a polymer of acrylamide, is used in various fields. Studies on functional materials using N-substituted polyacrylamide are actively being conducted. [4] For instance, Kizhakkedathu and coworkers have synthesized functional polymer brushes containing carbohydrate residues, which are used as an adsorbent for protein. [5] In addition, Nagase and coworkers developed thermoresponsive microfibers with enhanced mechanical properties by modifying mixed polymer microfibers with poly(N-isopropylamide). [6] Poly(N-isopropylamide) and its copolymer have also received a lot of research attention due to their coil-globule transition, which can be applied to various biomaterials. [7] Sharma et al. also formed coordination polymer thin films used for the recovery of Au from e-waste. This membrane is a coordination-based colorimetric film bearing Au(III) receptors prepared using two N-substituted acrylamides. [8] Chemists have also focused on developing synthetic polymer affinity reagents that can serve as alternatives to more traditional biobased reagents. Chou et al. have reported a library of hydrophobic N-alkylacrylamide monomers containing linear C4 hydrocarbon groups, positively charged monomers, N-isopropylacrylamide and synthetic copolymers NP containing N,N-methylene bis(acrylamide) that have an affinity for lipopolysaccharide (LPS), the lipophilic component of the outer membrane of Gramnegative bacteria. [9] Research on N-substituted polyacrylamides is still active in various fields, so the rapid and easy procurement of N-substituted acrylamide monomers is a key factor to support research in these fields.
Although acryl amide is synthesized via the hydration of acryl nitrile, N-substituted acryl amides are generally synthesized using Moureu's modified method. For instance, it is synthesized upon the reaction of acryloyl chloride and amine in the presence of a base, such as Et 3 N, EtN(i-Pr) 2 , NaHCO 3 , K 2 CO 3 and NaOH, under homogeneous conditions (Scheme 1). [1,2e,2f,2i,2j,2k] These methods can easily synthesize primary and secondary acryl amides. However, these homogeneous methods require neutralization or extraction of the base after the reaction, which produces a lot of waste.
As another method used for the construction of N-substituted amides, the Ritter reaction using nitrile and alcohols in the presence of acid is often employed (Scheme 2). [2a,2b,2d,2g,2h] However, the synthesis of N-substituted acryl amides was not been reported using the Ritter reaction other than the preparation of N-substituted amides.
For environmental reasons, it is highly desirable to replace homogeneous catalysts in organic synthesis with heterogeneous catalysts. Solid catalysts have many advantages such as ease of handling, reduction of plant corrosion and environmentally safe disposal. Therefore, many solid catalysts have been developed to date. [10] Recently, we reported the synthesis of functional amides in the presence of silica-gel supported sodium hydrogen sulfate (NaHSO 4 /SiO 2 ) utilizing the Ritter reaction. [11] In the paper, we realized the synthesis of N-substituted acryl amides. For the synthesis of N-substituted acryl amides, there are few reports using solid organic catalysts. [12] For example, studies using catalysts such as Montorillonite KSF, c-Fe 2 O 3 @SiO 2 -HClO 4 have been reported. The previously developed method shows promising results with good yields of the desired product. However, it is of increasing importance to overcome drawbacks such as the complexity of catalyst synthesis, and there is still a need to develop efficient catalytic systems for the synthesis of amides. Herein, we introduce two simple methods for the synthesis of N-substituted acryl amides using a solid inorganic base (Na 2 CO 3 /SiO 2 ) (method 1) and solid inorganic acid (NaHSO 4 /SiO 2 ) (method 2), respectively. Scheme 1. Synthesis of N-substituted acryl amides using base.
Scheme 2. Synthesis of N-substituted acryl amides by Ritter reactions.

Results and discussion
Synthesis of N-substituted acryl amides using a solid base supported reagent (method 1) The reaction of acryloyl chloride (1a) and aniline (2a) was employed as a model reaction to optimize the reaction conditions utilizing an inorganic solid supported base (Table 1). When 1 mmol of 1a and 2a in toluene in the presence of silica-gel supported sodium hydrogen carbonate (NaHCO 3 /SiO 2 ) was stirred at 0 C for 15 min, the expected product, N-phenyl acrylamide (3aa), was formed in 84% yield (entry 1). This reaction was performed at room temperature and gave 3aa in 88% yield (entry 2). Several inorganic bases were tested in the reaction. All inorganic bases were supported on silica-gel except for sodium and potassium hydroxide. Sodium and potassium hydroxide were supported on neutral alumina (Al 2 O 3 ) and used in the reaction. Reactions using silicagel supported potassium hydrogen carbonate (KHCO 3 /SiO 2 ), sodium carbonate (Na 2 CO 3 /SiO 2 ) and potassium carbonate (K 2 CO 3 /SiO 2 ) gave 3aa in good to excellent yield (entries 3-5), whereas the reactions using alumina supported sodium hydroxide (NaOH/Al 2 O 3 ) and potassium hydroxide (KOH/Al 2 O 3 ) gave 3aa in good yield (entries 6-7). Na 2 CO 3 /SiO 2 was most effective base for the reaction. When 1.2 equivalents of 1a was used in the reaction, 3aa was obtained in quantitative yield (entry 8). Therefore, we decided to use these conditions for our subsequent reactions.
The notable advantage of this procedure is that after the reaction, the used supported base can be removed via a simple filtration step. Hydrogen chloride, which was formed during the reaction was neutralized in the reaction mixture by Na 2 CO 3 /SiO 2 to form NaCl/SiO 2 . The excess 1a was neutralized by Na 2 CO 3 /SiO 2 and the formed sodium acrylate was adsorbed on SiO 2 to form CH 2 CHCOONa/SiO 2 . Both NaCl/SiO 2 and CH 2 CHCOONa/SiO 2 can be removed from the reaction vessel via filtration.
Several types of amines were used in the reaction under the optimized conditions, and the results are summarized in Table 2. The reaction using 4-iso-propylaniline (2b) gave its corresponding product (3ab) in 96% yield (entry 1). Whereas the reaction using diphenylamine (2c) did not provide the expected product (3ac). The reactivity of 2c toward 1a was low. In this reaction, 1a was completely consumed by Na 2 CO 3 /SiO 2 , but a large amount of 2c was recovered from the reaction mixture (entry 2). When diethyl amine was used in the reaction instead of 2c, the formation of N,N-diethylacryl amide (3ad) was observed in 72% yield by 1 NMR estimation. A series of butyl amines, namely n-butylamine (2e), sec-butylamine (2f) and tert-butylamine (2g), were used in the reaction. 2e and 2f reacted with 1a rapidly and the expected N-n-butyl acrylamide (3ae) and N-sec-butyl acrylamide (3af) products were formed in 96 and 90%, respectively. The reaction of 2g gave product 3ag in moderate yield.
Synthesis of N-substituted acryl amides using NaHSO 4 /SiO 2 via the Ritter reaction (method 2) Next, we attempted to develop a synthesis of N-substituted acryl amides using the Ritter reaction in the presence of NaHSO 4 /SiO 2 (Table 3). According to our previous studies, the reaction of acryl nitrile (4a) (2 mmol) and diphenyl methanol (5a) (3 mmol) was conducted at 80 C for 15 h in the presence of NaHSO 4 /SiO 2 (2.1 mmol) gives the expected N-diphenylmethyl acryl amide (6aa) product in 96% yield (entry 1). A similar reaction using bis(4-chlorophenyl)methanol (5b) gave its corresponding product (6ab) in 88% yield (entry 2). However, the product (6ac) yield of the reaction using bis(4-methylphenyl)methanol (5c) was lower than that of 6ab (entry 3). When bis(4methoxyphenyl)methanol (5d) was used in the reaction, the expected product (6ad) was not obtained. Instead, bis(4-methoxyphenyl)methane (7) and bis(4-methoxyphenyl)methanone (8) were formed in 40 and 46% yield, respectively (entry 4). The formation of 7 and 8 was a result of the dismutation of bis(4-methoxyphenyl)ether (5 00 d), which was formed from 5d and generated carbocation 5 0 d. 5 00 d can regenerate carbocation 5'd upon protonation, but in this case, dismutation to form 7 and 8 occurred in preference to the formation of 5 0 d. A plausible reaction pathway for the formation of 7 and 8 is shown in Scheme 3. Reactions using 4-substituted phenyl phenylmethanols 5e-5g also indicated a similar tendency to the reactions using 5b-5d. The yield of the reaction using 5e was the highest and the reaction using 5g did not give its corresponding product (6ag). We attempted to extend the scope of the reaction using 1-phenylalkylalcohols. When the reaction using 2 mmol of 1-phenylethanol (5h) was conducted, its corresponding product (6ah) was isolated in 11% yield only. Therefore, the reaction conditions were optimized for this reaction (Table 4). Increasing the amount of 4a led to an increase in  the yield of 6ah (entries 1-3). In these reactions, 5 00 h and styrene, which was formed from 5h, were observed. When the reaction was carried out using 4a in the absence of 1,2-dichloroethane (DCE), product 6ah was formed in up to 77% yield (entry 5). In this reaction, 5h was consumed in 5 h, but the yield of 6ah was lower than that of the reaction performed for 15 h (entry 6). When the reaction was carried out using a small amount of NaHSO 4 /SiO 2 , product 6ah obtained an 89% yield (entry 7). These "solvent free" conditions were used for our subsequent reactions using 1-phenylalkylalcohols (Table 5).

Conclusion
We have provided two simple methods for the synthesis of N-substituted acryl amides using Na 2 CO 3 /SiO 2 (method 1) and NaHSO 4 /SiO 2 (method 2). In the case of method 1, the highly pure expected products were obtained in good to excellent yield using filtration only. Hydrogen chloride, which was formed during the reaction, was neutralized in the reaction mixture by Na 2 CO 3 /SiO 2 to form NaCl/SiO 2 . The excess 1a was neutralized by Na 2 CO 3 /SiO 2 to form CH 2 CHCOONa/SiO 2 . Both NaCl/SiO 2 and CH 2 CHCOONa/SiO 2 could be removed from reaction vessel simply by filtration. In method 2, diphenyl methanols gave their corresponding products in good to excellent yield and the use of sec-benzylic alcohols gave their products in moderate to good yield.

Experimental
Preparation of Na 2 CO 3 /SiO 2 Silica gel [Wakogel C-200 (Wako Pure Chemical Ind. LTD.), 16.82 g] was added to a solution of sodium carbonate (30 mmol, 3.18 g) in distilled water and the resulting mixture was stirred at room temperature for 30 min. The water was removed using a rotary evaporator under reduced pressure and the resulting reagent was dried in vacuo (10 mmHg) at 160 C for 5 h.
Preparation of NaHSO 4 /SiO 2 SiO 2 (10 g) was added to a solution of NaHSO 4 ÁH 2 O (30 mmol, 4.14 g) in distilled water and the resulting mixture was stirred at room temperature for 30 min. The water was removed using a rotary evaporator under reduced pressure and the resulting reagent was dried in vacuo (10 mmHg) at 120 C for 5 h.
General procedure for the synthesis of N-substituted acryl amide Method 1: using Na 2 CO 3 /SiO 2 . 1a (1.2 mmol) was added dropwise to a mixture of amine 2 (1 mmol) and NaCO 3 /SiO 2 (1.0 mmol/g, 1.2 g) in Toluene (10 mL) at room temperature and stirred for 15 min. After the reaction, the used supported reagent was removed via filtration. The filtrate was evaporated to obtain the expected product 3.