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Abstract

Furfural and nitromethane were utilized as raw materials for the synthesis of the herbicide-safe agent Furilazole through the Henry reaction, nitro reduction and addition-cyclization-acylation. A comprehensive investigation into the involved reaction processes was conducted, leading to the identification of barium hydroxide octahydrate as the catalyst for the Henry reaction. The continuous use methodology of the excess catalyst was determined through TGA/DSC curve analysis, and a rational purification method for Henry reaction products was proposed. The nitro reduction reaction employed Pd/C catalysis, while the subsequent addition-cyclization-acylation reaction was achieved in a single step. Five impurities affecting the reaction process were identified, and their potential mechanisms of formation were postulated. Optimization of synthetic process conditions was carried out for all involved reactions. The structures of intermediates, impurities, and products were characterized using NMR, HRMS, TGA/DSC and FTIR.

Keywords

characterization Furilazole Henry reaction impurity analysis nitro reduction optimization

Introduction

Furilazole (Compound 1, structural formula in Figure 1) is a herbicide-safe agent of the dichloroacetamide class developed by Monsanto. When used in combination with herbicides such as isoxaflutole, mesotrione, sulfonylureas, imidazolinones, and halogenated amides, it effectively mitigates the phytotoxic effects on maize and cereal crops.¹ This compound plays a crucial role in increasing crop yields, garnering increasing attention from industry researchers.^2,3 Herbicide safe agents enhance crop metabolism and detoxification by elevating the comprehensive expression of cytochrome P450 (CYP450), glutathione (GSH), glutathione S-transferase (GSTs), and ATP-binding cassette (ABC) transport proteins, thereby neutralizing the phytotoxic effects of herbicides.⁴ Furilazole is primarily used in combination with pyridine carboxylic esters, benzamides, and other herbicides^5–7 to minimize the phytotoxicity on crops. In addition, it can be paired with pyrazole and aniline herbicides to control the adverse effects of plant pathogenic fungi, bacteria, and pests on crops.^8,9

Figure 1.

Furoxazole structure.

The literature reports two main categories of synthetic methods for Furilazole, both utilizing furfural as the starting material (Scheme 1). In 1989, Monsanto first reported the synthesis of Furilazole.¹⁰ Furfural underwent addition with trimethylsilyl cyanide at room temperature catalyzed by ZnI₂ to yield compound 2. Compound 2 was then reduced to compound 3 using lithium aluminum hydride in an anhydrous and oxygen-free ether system, followed by cyclization with acetone using 1,2-dichloroethane (DCE) as solvent to obtain compound 4. Compound 4 underwent acylation with dichloroacetyl chloride in the presence of a base (sodium hydroxide) and solvent dichloromethane (DCM) to yield compound 1, with an acylation yield of 60% and overall yield of 33%. In 1996, Mehrsheikh¹¹ followed a similar route, converting compound 3 to compound 4 in an anhydrous toluene containing p-toluenesulfonic acid. Triethylamine was employed as the base in the acylation reaction, resulting in overall yields ranging from 28% to 34%. In 2012, Huang¹² and Ding and Liu¹³ independently optimized this route by screening optimal ratios for various reactants, achieving an increased overall yield of 42% and Jia and Ma¹⁴ modified the original route by substituting ZnI₂ with boron trifluoride as the catalyst for the addition reaction and improving the addition and reduction reactions into a one-pot synthesis after 5 years.

Scheme 1.

Represents the reported synthetic routes for Furilazole in the literature.

Monsanto reported a new synthetic route for compound 1¹⁵ in 1995. Compound 5 reacted with acetone in a one-pot fashion under Ni catalysis and methyl tert-butyl ether (MTBE) as a solvent to undergo hydrogenation, cyclization, and subsequent acylation to yield compound 1, with a yield of 66% (calculated based on compound 5). Compound 5 itself could be obtained from furfural and nitromethane through the Henry reaction. In 2013, Ye et al.¹⁶ achieved a one-pot synthesis of Furilazole and its derivatives through the integration of cyclization (compound 4) and acylation reactions (compound 1) using 3 as starting material, resulting in a remarkable yield of 91%. Although this was a satisfactory yield, the use of large amounts of solvent benzene for removing the water generated in the cyclization is not suitable for industrial production.

Despite some existing literature on the synthesis of Furilazole, there is a lack of systematic studies, particularly regarding the recycling of catalysts and more optimal separation procedures. Given its excellent performance as herbicide safe agent, in-depth exploration of its synthesis process holds significant importance. In this study, we systematically investigated the synthesis process of Furilazole using the second route reported by Monsanto. This included the catalyst and impurity separation methods in the Henry reaction, the progress of the reduction reaction, and the process conditions for cyclization and acylation reactions in the preparation of Furilazole. Our aim is to develop an industrial-scale process that is easily reproducible, considering its application as herbicide-safe agent.

Results and discussion

Synthesis of α-(nitromethyl)-2-furanmethanol (5)

The Henry reaction, often catalyzed by bases, is a fundamental and widely utilized method for constructing carbon-carbon bonds. Commonly used bases include alkali metal hydroxides, carbonates, bicarbonates, alkaline earth metal oxides, alkaline earth metal hydroxides, copper(II) complexes, or organic bases like triethylamine.^17–24 While these catalysts can facilitate the Henry reaction, the required reaction times are often extended, leading to relatively low yields.¹² Moreover, soluble bases necessitate significant acid neutralization during post-treatment, resulting in substantial wastewater generation and lacking recyclability, which is unfavorable for environmentally friendly industrial production. To address environmental concerns related to neutralizing soluble bases, literature reports have proposed the use of solid base catalysts such as anion-exchange resins,^25,26 Mg/Al hydrotalcite,²⁷ inducing heterogeneous catalysis. This approach enables easy separation of the catalyst from the product through filtration, eliminating cumbersome post-treatment procedures. However, these catalysts have a limited application scope and may induce elimination reactions, generating substantial impurities such as nitroalkenes in some β-hydroxy nitro compounds. Considering industrial production requirements and building upon existing literature, we further screened suitable catalysts for the Henry reaction to prepare compound 5. We designed a recycling plan for the selected catalyst, aiming to enhance its practical significance. In light of numerous reports on conventional alkali metal hydroxide-catalyzed Henry reactions, we selected organic bases such as tetramethyl ethylenediamine (TMEDA),²⁸ dimethylbiguanide (DIABEX),²⁹ potassium tert-butoxide (t-BuOK),³⁰ tetramethylguanidine (TMG),³¹ and inorganic bases including anhydrous potassium carbonate (K₂CO₃),³² sodium iodide (NaI), cesium carbonate (Cs₂CO₃), KI/I₂/K₂CO₃,³³ barium hydroxide octahydrate (Ba(OH)₂∙8H₂O),³⁴ as well as solid base resins 201 × 4 [Aimei Kejian (China) Biopharmaceutical Co., Ltd, http://www.amicogenchina.cn] and HND-062 (Jiangyin Nanda Synthetic Chemistry Co., Ltd, http://www.amberlyst.net) as catalysts (Scheme 2). The results of the Henry reaction are presented in Table 1.

Scheme 2.

Henry reaction.

Table 1.

Influence of alkaline catalysts on Henry reaction yields.^a

Entry	Alkaline Catalysts	Compound 5 Yields^b (%)
1	TMEDA	34.6
2	DIABEX^c	30.6
3	TMG	34.6
4	t-BuOK	61.8
5	K₂CO₃	63.6
6	NaI	35.2
7	Cs₂CO₃	38.5
8	KI/I₂/K₂CO₃	36.7
9	Ba(OH)₂∙8H₂O	78.9
10	Resins 201 × 4	43.1
11	Resins HND-062	40.4

TMEDA: tetramethyl ethylenediamine; TMG: tetramethylguanidine; K₂CO₃: potassium carbonate.

Reaction condition: furfural 2.00 g, nitromethane 24.41 g, catalyst loading: entries 1-9 is 0.13 eq, entries 10-11 is 20 wt% (based on furfural), c_furfural = 2 mol/L in THF at 24 °C for 12 h, stirring speed of 400 r·min⁻¹.

Calculated by HPLC external standard method determined the content of compound 5.

DIABEX was prepared by Metformin HCl: 0.02 g/mL NaOH ethanol solution, n_NaOH: n_{Metformin HCl} = 1:1, room temperature for 1 h, filter and concentrate.

Data in Table 1 indicate that the yields of organic bases such as tetramethyl ethylenediamine (pK_b 3.6), dimethylbiguanide (pK_b 1.6), and tetramethylguanidine (pK_b −1.2) are relatively low, it is mainly due to the elimination of hydroxyl group under strongly alkaline conditions. Moreover, tetramethyl ethylenediamine exhibits significant exothermicity during the reaction, posing certain risks. Potassium tert-butoxide (pK_b −3) among the organic bases demonstrates higher catalytic efficiency, since potassium tert-butanol dissolves in the reaction solution and participates in the reaction, it cannot be recovered for continuous use. While using alkaline resins as catalysts facilitates post-reaction separation, the selected resin types result in relatively low yields of compound 5. Inorganic bases exhibit milder catalytic reactions; however, the catalytic efficiency of sodium iodide, cesium carbonate, and the KI/I₂/K₂CO₃ system is not ideal. The catalytic reaction of barium hydroxide octahydrate gave the highest yield, attributed to the crystalline water in the catalyst can be dissolved in THF, allowing a small amount of barium hydroxide to dissolve in the reaction solution³⁴ to enhance the basicity of the reaction system. The alkaline enhancement promotes the Henry reaction. In addition, the limited solubility of barium hydroxide in water (3.89 g/100 g at 20 °C) ensures a moderate alkalinity in the system. As barium hydroxide remains in solid form during the reaction, the biphasic reaction system helps maintain the stability of compound 5 and reduces the likelihood of elimination reactions. The barium hydroxide octahydrate remains in solid form after the reaction, allowing for direct filtration and separation from the reaction system, facilitating the recycling of the catalyst.

The repeated use of catalysts is a crucial consideration in industrial production. In Henry reaction, barium hydroxide octahydrate catalyst is clearly excessive, they are filtered out directly after the reaction and dried. Upon attempting to continue to use the post-use barium hydroxide octahydrate catalyst in the next Henry reaction, it was observed that the catalytic efficacy was lost. Upon XRD of the post-use catalyst (SI Supplemental Figure S1), it was noted that it had transformed from its initial crystalline particle form into a powder-like crystalline structure. It is hypothesized that the crystal structure of the catalyst undergoes a change after the reaction, significantly impacting its catalytic ability. To investigate the primary factors influencing the recyclability of barium hydroxide octahydrate, the catalyst before and after use was characterized using TGA/DSC, as shown in Figure 2.

Figure 2.

TGA/DSC of barium hydroxide octahydrate pre-use and post-use.

Seen from Figure 2, the TGA/DSC curve of pre-used barium hydroxide octahydrate, exhibits a significant broad endothermic peak around 86.76 °C, attributed to the gradual loss of crystalline water, it indicates the loss of 7 crystalline water molecules at this stage. A small endothermic peak at 121 °C corresponds to the loss of an additional crystalline water molecule, which is consistent with literature reports.³⁵ The post-use catalyst shows a notably lower first endothermic peak (69.79 °C), indicating adsorption of the effect of a small amount of the residual THF solvent. Moreover, the amount of crystal water in used hydrated barium hydroxide changes and some crystal water lost. We found that it is the crystal water in the hydrated barium hydroxide that has a great influence on the reaction and is also the decisive factor for the continued use of the separated barium hydroxide after the reaction. It is hypothesized that in the reaction system, the crystalline water in barium hydroxide octahydrate can dissolve a suitable amount of barium hydroxide in THF, ensuring the OH⁻ concentration in the system meets the requirements for catalyzing the Henry reaction. The partial loss of crystalline water in used barium hydroxide affects its catalytic efficacy, emphasizing the importance of an appropriate water content for the catalyst’s continuous use.

Based on this, a plan for the consecutive use of the post-use catalyst was designed. As a base supplier, the catalyst will lose mass after a reaction, through the comparison of catalyst mass before and after the reaction, it is proved that the catalyst will normally lose 7% per reaction. Therefore, for each catalyst reuse, 7% of the catalyst needs to be replenished. The specific experiments are as follows. The catalyst recovered from the previous reaction replenishes the water volume of 4 crystal waters, and replenishes 7% of the new catalyst. The total amount of catalyst was controlled as 9% molar ratio to furfural. The results demonstrate the practical feasibility of this approach, with the average yield of compound 5 obtained through three consecutive uses of the recovered catalyst being 96.8% ± 1.1.

During the Henry reaction, two impurities directly affecting the yield of compound 5 were observed (Impurity A and B). Through isolation and characterization via ¹H NMR, MS, and IR, their structures were determined to be 2-(2-nitroethenyl)-furan and 2-(2-furanyl)-1,3-dinitropropane, respectively, as shown in Figure 3. Clearly, impurity A is formed through the elimination reaction of the hydroxyl group at the nitro β-position of 5, while impurity B results from the continuation of the Michael addition reaction between impurity A and the raw material nitromethane under alkaline conditions.

Figure 3.

Structure and formation mechanism of impurity A and B.

Impurity A, due to its conjugated double bond, exhibits greater stability than compound 5. The reaction temperature and post-treatment temperature are crucial factors in its formation, as indicated by the stability experiment results for compound 5 shown in Table 2. Table 2 demonstrates that the content of 5 decreases by 5.4% within 8 hours of storage at 5 °C, indicating that the storage temperature should be controlled below 5 °C. Within 2 h of storage at 15 °C, the content decreases of 5 by 9.0%, suggesting that the post-treatment at 15 °C should be limited to within 1 h. As for the reaction temperature, it should not be higher than 25 °C, otherwise the dehydration of 5 is more obvious, affecting the yield.

Table 2.

Stability test of compound 5 and impurity A.

Entry	T (°C)	t (h)	Concentration^a (mg·mL⁻¹)
Entry	T (°C)	t (h)	Compound 5	Impurity A
1	−5	0	0.1640	0.0017
2	−5	1	0.1615	0.0018
3	−5	2	0.1615	0.0018
4	−5	4	0.1607	0.0020
5	−5	8	0.1600	0.0026
6	5	0	0.0853	0.0011
7	5	1	0.0818	0.0022
8	5	2	0.0819	0.0022
9	5	4	0.0817	0.0025
10	5	8	0.0807	0.0030
11	15	0	0.0845	0.0009
12	15	1	0.0843	0.0028
13	15	2	0.0769	0.0039
14	15	4	0.0737	0.0048
15	15	8	0.0713	0.0071
16	25	0	0.0826	0.0029
17	25	1	0.0795	0.0049
18	25	2	0.0753	0.0069
19	25	4	0.0742	0.0103
20	25	8	0.0614	0.0166

HPLC external standard method.

Due to the presence of impurity A being a prerequisite for the generation of impurity B, the amount of raw material nitromethane is a primary factor in the further generation of B.³⁶ Therefore, an investigation was conducted on the effect of ratio of barium hydroxide octahydrate and nitromethane on the yield of 5, and the results are presented in Table 3.

Table 3.

Impact of the molar ratio of the reacting materials on the Henry reaction.^a

Entry	n_furfural/n _{Ba(OH)2·8H2O}/n_nitromethane	Yield of compound 5^b (%)
1	1:0.01:20	17.1
2	1:0.03:20	73.4
3	1:0.05:20	78.9
4	1:0.07:20	79.5
5	1:0.09:20	81.4
6	1:0.11:20	79.8
7	1:0.13:20	78.9
8	1:0.09:2	54.4
9	1:0.09:4	65.1
10	1:0.09:6	81.4
11	1:0.09:8	81.3
12	1:0.09:10	81.3

Reaction condition: furfural 2.00 g and 10.0 mL THF at 20 °C for 12 h, stirring speed of 400 r·min⁻¹.

Calculated by HPLC external standard method determined the content of compound 5.

As seen from Table 3, with the molar ratio of barium hydroxide octahydrate increases, the concentration of OH⁻ in the reaction system enhances, and the yield of compound 5 also increases. With an increase in the molar ratio of nitromethane, the yield of compound 5 continues to rise because increasing the amount of raw material is conducive to the production of products. However, after reaching a certain degree, the yield trend does not increase obviously with the increase of catalyst and nitromethane. Since excessive catalyst and nitromethane can lead to increased difficulty in post-treatment, a lower ratio is selected at an almost stable yield. Therefore, the reasonable molar ratio of furfural, catalyst and nitromethane is 1:0.09:6.

Under the catalysis of barium hydroxide octahydrate, the effects of other process conditions such as stirring speed, reaction temperature, and reaction time on the yield of compound 5 are presented in Table 4.

Table 4.

Effects of reaction conditions on the yield of compound 5.^a.

Entry	Stirring speed (r·min⁻¹)	T (°C)	t (h)	Yield^b (%)
Entry	Stirring speed (r·min⁻¹)	T (°C)	t (h)	Compound 5	Impurity A
1	300	20	3	54.8	1.85
2	400	20	3	55.2	1.79
3	500	20	3	67.5	2.17
4	600	20	3	57.2	2.01
5	500	0	3	18.7	0.16
6	500	5	3	25.7	0.30
7	500	10	3	46.6	0.94
8	500	15	3	53.4	1.89
9	500	25	3	63.8	2.09
10	500	20	6	97.9	1.82
11	500	20	9	95.4	2.04

Reaction condition: furfural 2.00 g, nitromethane 7.32 g, catalyst 0.568 g and 10.0 mL THF.

Calculated by HPLC external standard method determined the content of compound 5 and impurity A.

From Table 4, it can be observed that the improvement in yield is significant within the stirring speed range of 300 to 600 r·min⁻¹. This is because increasing the stirring speed enhances mass transfer in the reaction, thereby improving the reaction yield. The data indicate that increasing the temperature can lead to elimination reactions, resulting in an increased yield of impurity A. Therefore, the choice of temperature is very important, comprehensive consideration, the best yield of 5 at 20 °C, and prolong the reaction time to get the best yield of 5.

In the Henry reaction, to minimize the generation of impurity B, the quantity of nitromethane should be reduced, resulting in some unreacted furfural. While vacuum distillation can remove the majority of unreacted furfural and nitromethane, the high distillation temperature can lead to a substantial increase in impurity A with reducing the yield of compound 5. Due to its high boiling point (222.7 ± 15 °C/760 mmHg), impurity A is difficult to separate from compound 5 by distillation; however, the presence of impurity A will affect the purity of the subsequent hydrogenation products. Therefore, investigating methods to remove unreacted furfural and impurity A is crucial. Sodium bisulfite, due to its ability to undergo addition reactions with the aldehyde group of furfural and undergo a similar Michael addition reaction with impurity A,³⁷ is applied in the post-treatment of the reaction. Because it is difficult to produce residual furfural and excessive impurity A under optimized reaction conditions, in order to study this removal method in detail, the sample was prepared by staying the reaction product at high temperature to left it to age and gain the sample containing impurity A, and then add an appropriate amount of furfural. The specific operation was as follows. The sample is stirred with a 0.5 g/mL sodium bisulfite solution at 15 °C. After filtered, the filtrate was detected, and the result is shown in Table 5.

Table 5.

Optimization of removing Furfural and Impurity A with sodium bisulfite.^{a, b,c}

Entry	t (h)	Sodium bisulfite dosage (mL)	Furfural content (%)	Impurity A content (%)	Compound 5 content (%)
1	0	0	15.3	9.83	71.5
2	3	10	6.04	0.64	90.9
3	6	10	2.31	0.24	94.5
4	9	10	2.34	0.26	94.0
5	12	10	2.32	0.25	94.1
6	6	20	2.33	0.24	94.3
7	6	30	2.32	0.25	93.8

In each experiment, 10.0 g sample.

The sample is prepared by the process as follows. The reaction product was placed at 25 ^oC for 6 h, and then add an appropriate amount of furfural.

HPLC external standard method.

Table 5 data indicate that the contents of furfural and impurity A decreased rapidly after the reaction for 6 h, and then the contents of furfural and impurity A in the reaction solution tended to be stable. This demonstrates the effectiveness of the method in purifying the Henry reaction solution, increasing the ratio of compound 5 to impurity A and furfural. The treated reaction solution can be directly subjected to subsequent reduction reactions. The filtered furfural-sodium bisulfite complex can be decomposed under acidic conditions. By adjusting the pH of the reaction solution, furfural can be recovered from the organic phase as a raw material for the Henry reaction.

α-(Aminomethyl)-2-furanmethanol (3)

In the nitro reduction reaction, common catalytic methods such as iron powder, hydrazine hydrate, and sulfides have good yields but cause significant environmental pollution, making them unsuitable for industrial production. The use of metal catalysts for catalytic hydrogenation is characterized by high reducibility and low pollution.³⁸ Different metal catalysts were used to catalyze the reduction of 5 (scheme 3), and reaction conditions were investigated, as shown in Table 6.

Scheme 3.

Nitro reduction reaction.

Table 6.

Experimental data for nitro reduction conditions.^a

Entry	Cat.	m₅/m_cat.	Solvent	H₂ (kg∙cm²)	V (mL)	Compound 3 Yield^b (%)
1	5%Pd/CaCO₃	1:0.05	IPA	8	400	0
2	5%Pd/BaSO₄	1:0.05	IPA	8	400	0
3	5%Pd/C	1:0.05	IPA	8	400	9.29
4	5%Pt/C	1:0.05	IPA	8	400	7.29
5	Raney Ni	1:0.05	IPA	8	400	4.33
6	10%Pd/C	1:0.05	IPA	8	400	6.50
7	5%Pd/C	1:0.08	IPA	8	400	14.1
8	5%Pd/C	1:0.10	IPA	8	400	22.2
9	5%Pd/C	1:0.12	IPA	8	400	47.8
10	5%Pd/C	1:0.14	IPA	8	400	23.3
11	5%Pd/C	1:0.12	MeOH	8	400	55.0
12	5%Pd/C	1:0.12	EtOH	8	400	50.4
13	5%Pd/C	1:0.12	H₂O	8	400	4.2
14	5%Pd/C	1:0.12	MeOH	5	400	52.3
15	5%Pd/C	1:0.12	MeOH	10	400	56.0
16	5%Pd/C	1:0.12	MeOH	15	400	54.8
17	5%Pd/C	1:0.12	MeOH	20	400	40.8
18	5%Pd/C	1:0.12	MeOH	10	300	48.4
19	5%Pd/C	1:0.12	MeOH	10	500	55.6
20	5%Pd/C	1:0.12	MeOH	10	600	55.0

Reaction condition: 50.0 g compound 5, temperature is 40 °C for 50 h.

Calculated by HPLC external standard method determined the content of compound 3.

Table 6 shows that Raney nickel, Pt/C, and Pd/C all have certain catalytic effects, with Pd/C exhibiting significantly better catalytic performance than Pd loaded on other carriers such as calcium carbonate and barium sulfate. The yield of compound 3 under different pressures was obtained from the data (entries 11 and 14 to 17). When the pressure is higher than 10 kg/cm², the higher the pressure, the lower the yield of compound 3. Possibly due to the easier decomposition of intermediate nitroso compounds or hydroxylamine into impurities under high pressure, therefore higher reaction pressure is unfavorable for nitro reduction. Since the solubility of compound 5 in water is low, the reduction effect in water as a solvent is poor, while methanol, with better solubility for 5, provides a more stable reaction yield when used as a solvent. 5% Pd/C is the catalyst for the reduction reaction, and the effects of reaction time and temperature on the reaction yield under the conditions of methanol as the solvent are shown in Table 7.

Table 7.

Effect of reaction time and temperature on the yield.^a.

Entry	Time (h)	Temperature (°C)	Yield of compound 3^b (%)
1	30	40	31.0
2	40	40	32.3
3	50	40	58.4
4	60	40	53.4
5	50	50	38.2
6	50	60	65.3
7	50	80	58.3

Reaction conditions: 50.0 g compound 5, 200 mL methanol, hydrogenation pressure 10.0 kg/cm², 6.00 g 5%Pd/C.

Calculated by HPLC external standard method determined the content of compound 3.

In Table 7, it can be observed that, under constant conditions, extending the reaction time increases the yield. The reaction involving the reduction of nitro groups to nitrosyl compounds or oximes is rapid, while the subsequent hydrogenation to amines is a slow reaction stage, playing a crucial role in the rate-determining step of the entire hydrogenation process. As this step is relatively slow, many impurities are generated during this stage. Reaction temperature is a key factor influencing the product yield, and moderately increasing the temperature while prolonging the reaction time is advantageous for the forward movement of this reaction.

During the reduction reaction, impurities C and E were separated through column chromatography, and their structures are shown in Figure 4. Based on ¹H NMR analysis, impurity C was identified as the reduced intermediate α-OH furan oxime, which is in tautomeric equilibrium with the β-OH furan nitrosyl compound, formed by eliminating one molecule of water after the addition of one molecule of H₂, and because of its poor stability, it is too difficult to isolate to do other characterizations. Impurity E was confirmed as 2,5-bis(tetrahydrofuran-2-yl)pyrazine by ¹H NMR,¹³C NMR HSQC, HMBC, and ¹H-¹H COZY. It is speculated that the formation mechanism of compound 6 is as follows. Compound 3 was obtained by catalytic hydrogenation of compound 5 at Pd/C. Under Pd/C conditions, the hydroxyl group of compound 3 is dehydrogenated to carbonyl group (compound 6), and the two-molecule compound 6 undergoes Schiff base reaction to form a nitrogen-containing six-membered ring (intermediate state), which is aromatized to form a pyrazine ring (impurity E) under Pd/C. It was observed that the generation of impurity E is significantly influenced by temperature and pressure, with increased pressure favoring its formation because high pressure is more conducive to dehydrogenation. And isolated and identified the structure of compound D as 2,5-di(furan-2-yl)pyrazine by ¹H NMR and HPLC-MS.

Figure 4.

Mechanism of tautomeric equilibrium for impurity C and formation of E.

Due to the high purity requirements for the cyclization reaction, purification of 3 is necessary through recrystallization. The recrystallization solvent of 3 was determined by the investigation on the solubility of different solvents. It was determined by XRD that the crystal forms of compound 3 did not change after recrystallization in selected different solvents (SI Supplemental Figure S2). Solubility of compound 3 in selected different solvents was measured by HPLC method, and the result was shown in Figure 5. It demonstrates that although methanol exhibits the most significant variation in solubility with temperature, its solubility for 3 is higher at low temperatures, leading to reduced recrystallization yields. Petroleum ether, with minimal solubility for 3 and no significant changes with temperature, is not suitable as a crystallization solvent. While the solubility of 3 in isopropanol does not vary as dramatically with temperature as methanol, its solubility for 3 is low at low temperatures, facilitating higher recrystallization yields. Therefore, isopropanol is a more suitable crystallization solvent for compound 3. Experimental verification of recrystallization in isopropanol yielded a purity of 99.86% ± 0.03%.

Figure 5.

Solubility of compound 3 in different solvents.

The synthesis of furalaxizole (1)

During the process of synthesizing 1 using the one-pot method (scheme 4), a significant impurity was identified. Through recrystallization with dichloromethane, impurity F was obtained, and its structure was confirmed by NMR and HRMS to be 2,2-dichloro-N-[2-(2-furanyl)-2-hydroxyethyl]acetamide (Figure 6). It is speculated that its formation may occur through two pathways. One is due to the incomplete condensation reaction between compound 3 and acetone, resulting in an excess of compound 3 in the system, and direct reaction with dichloroacetyl chloride to generate F. The other is that compound 4 undergoes a reverse condensation reaction during the acylation process influenced by hydrogen chloride in the system, leading to the formation of compound 3, followed by the reaction of 3 with dichloroacetyl chloride to produce impurity F. To validate the reaction pathway, a reaction was conducted between 99% pure compound 4 and dichloroacetyl chloride, monitoring the reaction revealed the generation of a certain amount of impurity F (>20%), and the quantity of F increased with the progression of the reaction, demonstrating that indeed, the decomposition of 4 during the reaction leads to the generation of F. According to the reaction mechanism, the decomposition of compound 4 must involve water. In order to verify this inference, compound 4 was exposed to dry hydrogen chloride and detected after a certain period of time. No formation of compound 3 was found, which proved that compound 4 had good stability in the hydrogen chloride system. Then, a small amount of water was added to the system and compound 3 was detected a few minutes later. This means that the impurity F was indeed caused by the hydrolysis of compound 4 under the reaction conditions.

Scheme 4.

Synthesis of Furoxazole.

Figure 6.

Formation mechanism of impurity F.

The literature reports^39,40 that oxazole derivatives can easily undergo isomerization and ring-opening reactions under alkaline conditions, leading to the formation of Schiff bases and other derivative compounds. Therefore, the reaction conditions play a significant role in the cyclization reaction. To explore the optimal reaction conditions for this process, various factors such as the binding agent, solvent type, reaction temperature, duration, and the ratio of reactants were screened, and the results are summarized in Table 8.

Table 8.

Experimental data of acylation reaction and cyclization reaction.

Entry	Base	Solvent	n₃/n_solvent	Compound 1 Yield^a,b (%)
1	Pyridine	CHCl₃	1:10	0
2	33%NaOH	CHCl₃	1:10	61.5
3	TEA	CHCl₃	1:10	33.0
4	NH₄OH	CHCl₃	1:10	16.5
5	33%NaOH	CHCl₃	1:10	72.4
6	33%NaOH	Toluene	1:10	42.2
7	33%NaOH	ACN	1:10	44.0
8	33%NaOH	EAOH	1:10	37.6
9	33%NaOH	Acetone	1:10	35.8
10	33%NaOH	DCM	1:10	71.3
11	33%NaOH	DCM	1:4	46.3
12	33%NaOH	DCM	1:6	65.8
13	33%NaOH	DCM	1:8	72.9

DCM: dichloromethane.

Calculated by HPLC external standard method determined the content of compound 1.

Reaction condition: 10.0 g compound 3, Entries 1 to 4: 22.9 g acetone, 14.0 g dichloroacetyl chloride and 7.59 g base at 0 °C for 2 h; Entries 5 to 13: 31.7 g acetone, 15.1 g dichloroacetyl chloride and 6.80 g base at –5 °C for 3.5 h.

In Table 8, it can be observed that compared to other base, the reaction with 33% sodium hydroxide yields a higher conversion rate. The primary impurity monitored during the reaction is F. The reaction system with 33% sodium hydroxide is biphasic, effectively reducing the ring-opening of 4 and the formation of F, thereby enhancing the reaction yield. Although both chloroform and DCM have achieved better yields, due to the toxicity of chloroform and the fact that chloroform forms highly active carbene under strongly alkaline conditions, DCM is a more suitable solvent for industrial production.

The original literature mentions that the crude product of 1 was recrystallized with isopropyl alcohol and water (1:1), resulting in a gas phase purity of 94.8%. To further enhance the purity of 1, the recrystallization solvent of 1 was determined by the investigation on the solubility of different solvents through the Laser Dynamic Analysis method. First, the recrystallized crystal forms of 1 in different solvents were determined by XRD characterization. The result is shown in Figure 7. Figure 7 indicates that the crystal structure of 1 remains unchanged after crystallization in five solvents. Subsequently, the solubility of 1 in these solvents was determined using laser dynamic analysis (SI Supplemental Table S1), and the solubility curves are depicted in Figure 8. From Figure 8, it can be observed that the solubility of 1 in tetrahydrofuran varies the most with temperature, but it is relatively high at low temperatures, which may lead to product loss. Among the other four solvents, the solubility of 1 in ethyl acetate exhibits the most significant variation with temperature and is lower at lower temperatures, making it more suitable as a recrystallization solvent for 1.

Figure 7.

XRD pattern of compound 1 crystalline solid in different solvents.

Figure 8.

Solubility of compound 1 in different solvents determined by Laser Dynamic Analysis method.

Table 9 shows that due to the higher solubility of compound 1 in THF at low temperatures, the recrystallization product yield is indeed lower, and the content is also relatively low. This could be attributed to the relatively high solubility of impurities in THF. Recrystallization of 1 in ethyl acetate results in a significantly higher product content compared to THF, with higher yields.

Table 9.

Validation data for recrystallization of compound 1.^a

Solvent	Content (%)	Recrystallization yield (%)
THF	90.6	74.1 ± 0.11
EA	99.7	97.4 ± 0.18

Content of 1 in the crude product is 75.3%, and the feeding amount is 5.00 g.

Conclusion

Compound 1 was synthesized through Henry reaction, nitro reduction, and one pot of cyclization and acylation reactions. In the Henry reaction, the use of barium hydroxide octahydrate for biphasic catalysis proved effective. With the help of TGA/DSC study, the method to continue using barium hydroxide octahydrate was determined and the recovered barium hydroxide can continue to participate in the reaction as long as the appropriate amount of water is added to the reaction, significantly saving costs. The purification method using sodium bisulfite also led to a noticeable increase in the ratio of compound 5 to impurity A and furfural. By controlling the temperature, reaction conditions and the amount of raw material, the formation of impurities A and B is inhibited, and the yield of 5 is further improved. Experimental results demonstrate that Pd-catalyzed hydrogenation is the most effective, and the one-pot method for cyclization and acylation reactions is more suitable for industrial production. Based on the solubility behavior study, recrystallization of the crude product 1 in ethyl acetate showed significantly better results than reported in the original literature, improving efficiency and increasing yields. NMR, HRMS and DSC were used to confirm the structure of 5 impurities. The formation mechanism of impurities was speculated, which is helpful to restrain the formation of impurities by controlling reaction conditions, and further improve the yield.

Experimental section

Furfural, dichloroacetyl chloride, and isopropanol were purchased from Aladdin, while barium hydroxide octahydrate and anhydrous magnesium sulfate were obtained from Aladdin. All other reagents were from Tianjin Damao Chemical Reagent Company and used without further purification. FTIR (FTS 135, KBr pellet) from BIO-RAD (America) was used for infrared analysis. NMR spectra were recorded on a Bruker Avance (DRX-500) NMR spectrometer (German). The melting point of the compounds was obtained by the differential scanning calorimeter (YND-BM2) of Shanghai Yingnuo Precision Instrument Company (China), and the molecular weight of the product was obtained by FTICR-MS (7.0T) of IonSpec (America). TGA/DSC analysis was performed using thermogravimetric thermal difference analyzer (SDT-Q600) from TA corporation (America). The solubility of the compound 3 and 1 was determined by Agilent High Performance Liquid Chromatogram (1260) (America) and DLS (SZ-19) of Tianjin Qidong Technology (China), respectively. Crystalline was determined by X-Ray Diffractometer (Smartlab 9 KW) of Rigaku (Japan). Stainless steel autoclave CJ (K)-1 from Weihai Xinyuanhua Machinery (China).

Reaction monitoring was performed using an Agilent 1260 liquid chromatography system. Detection conditions for compound 5 were as follows: mobile phase, methanol: water = 2:3 (V/V); C18 column; flow rate, 1.0 mL/min; injection volume, 5 μL. Conditions for compound 3 were: mobile phase, acetonitrile: 0.02 mol/L potassium dihydrogen phosphate aqueous solution = 8:2 (V/V); C18 column; flow rate, 1.0 mL/min; injection volume, 5 μL. Conditions for compound 1 were: mobile phase, acetonitrile: 0.1% formic acid aqueous solution = 3:2 (V/V); C18 column; flow rate, 1.0 mL/min; injection volume, 5 μL.

Synthesis of α-(nitromethyl)-2-furanmethanol (5)

Furfural (2.00 g, 0.02 mol), nitromethane (7.32 g, 0.12 mol), barium hydroxide octahydrate (0.57 g, 0.09 mol), and 10 mL THF were successively added to a 100 mL reaction flask and stirred at 20 °C for 6 h. After completion of the reaction, the mixture was filtered, and the resulting yellow concentrated solution was concentrated. Saturated sodium bisulfite aqueous solution was added to the concentrated solution, stirred at 15 °C for 6 h, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain compound 5.

IR (KBr), ν, cm⁻¹: 3300-3400, 3650, 2924, 1384, 1557, 1261, 1102. ¹H NMR (DMSO-d₆, 400 MHz, δ: ppm): 7.649 (m, 1H), 6.451 (m, 1H), 6.432 (m, 1H), 6.225 (s, 1H), 5.255 (m, 1H), 4.960-4.964 (m, 2H). MS (m/z): 180.0. Consistent with literature values.¹²

Impurities A

Through column chromatography separation of the above concentrated mixture, a colorless oily liquid impurity A was obtained.

IR (KBr), ν, cm⁻¹: 1100-1300, 1560, 1350, 1610-1640, 3010-3100. M.p. 76.51 °C. ¹H NMR (DMSO-d₆, 500 MHz, δ: ppm), 8.05-8.02 (m, 2H), 7.78 (m, 1H), 7.29 (m, 1H), 6.77 (m, 1H). MS (m/z): 140.0. Consistent with literature values.⁴¹

Impurity B

Through column chromatography separation of the above concentrated mixture, a yellow oily liquid impurity B was obtained.

¹H NMR (CDCl₃, 400 MHz, δ: ppm), 7.42 (dd, J = 1.8, 0.6 Hz, 1H), 6.37 (dd, J = 3.3, 1.9 Hz, 1H), 6.31 (d, J = 3.3 Hz, 1H), 4.93-4.75 (m, 4H), 4.47 (p, J = 6.7 Hz, 1H). Consistent with literature values.⁴²

Synthesis of α-(aminomethyl)-2-furanmethanol (3)

In a high-pressure reactor (Stainless steel autoclave, CJ (K)-1), compound 5 (50.0 g, 0.32 mol), 10 mL methanol, and 5% Pd/C (6.0 g, 0.051 mol) were successively added, pressurized to 1.0 MPa, and reacted at 60 °C for 40 h. After filtration to remove the Pd/C catalyst, the filtrate was concentrated to yield a yellow solid, which was recrystallized with isopropanol to obtain compound 3.

M.p. 88.38 °C. ¹H NMR (DMSO-d₆, 500 MHz, δ: ppm), 7.57 (d, J = 1.7 Hz, 1H), 6.40 (dd, J = 3.2, 1.8 Hz, 1H), 6.26 (d, J = 3.1 Hz, 1H), 4.42 (dd, J = 7.5, 4.9 Hz, 1H), 2.84-2.68 (m, 2H). MS (m/z): 127.06. Consistent with literature values.¹²

Impurity C

Column chromatography separation of the crystallization mother liquor of compound 3 yielded a white needle-shaped solid impurity C.

¹H NMR (DMSO-d₆, 500 MHz, δ: ppm), 11.84 (s, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.21 (s, 1H), 6.65 (s, 1H), 3.19 (s, 1H).

Impurity D

M.p. 179.35 °C. ¹H NMR (CDCl₃, 500 MHz, δ: ppm), 8.95 (s, 2H), 7.64 (dd, J = 0.5, 1.5 Hz, 2H), 7.17 (dd, J = 0.5, 3 Hz, 2H), 6.62 (dd, J = 2, 3.5 Hz 2H). HPLC-MS (m/z): 212.81. Consistent with literature values.⁴³

Impurity E

Petroleum ether was added to the reaction solution of compound 3, stirred, and the petroleum ether phase was separated. After concentration and crystallization, a white powder-like solid impurity E was obtained.

M.p. 114.46 °C. ¹H NMR (CDCl₃, 500 MHz, δ: ppm), 8.56 (s, 2H), 4.98 (s, 2H), 4.05 (d, J = 5 Hz, 2H), 3.91 (d, J = 5 Hz, 2H), 2.35 (m, 2H), 2.05-1.92 (m, 6H). ¹³C NMR (CDCl₃, 125 MHz, δ: ppm), 156.26, 141.15, 79.65, 69.18, 32.76, 25.75. HSQC (CDCl₃, 500 MHz, δ: ppm), δ 141.15 carbon is correlated with δ 8.56 hydrogen; δ 79.65 carbon is correlated with δ 4.98 hydrogen; δ 69.18 methylene carbon is correlated with δ 4.05, δ 3.92 hydrogen; δ 32.76 methylene carbon is correlated with δ 2.35, δ 1.96-1.93 hydrogen; δ 25.75 methylene carbon is correlated with δ 1.96-1.93 hydrogen. HMBC: (CDCl₃, 500 MHz, δ: ppm), δ 8.56 hydrogen is associated with δ 156.26, δ 141.15 carbon; the hydrogen of δ 14.98 is correlated with the carbon of δ 156.26, δ 144.15, δ 69.18, δ 32.76, δ 25.75; δ 4.04 and δ 3.92 hydrogen is associated with δ 79.15, δ 32.76, δ 25.75 carbon; the hydrogen of δ 2.34 and δ 1.95 is associated with the carbon of δ 79.15, δ 69.18, δ 32.76, and δ 25.75. ¹H-¹H COZY: (CDCl₃, 500 MHz, δ: ppm), the hydrogen of δ 4.97 correlates with the hydrogen of δ 2.34 and δ 1.95. HRMS (m/z): 220.1282 [M + H]⁺ Calcd. for C₁₂H₁₆O₂N₂ 220.1212.

Synthesis of Furanidin (1)

Compound 3 (10 g, 0.09 mol), acetone (32 g, 0.55 mol), and DCM (15.1 g, 0.18 mol) were added to a 100 mL reaction flask. Reflux was carried out at 40 °C for 1 h, followed by cooling to –5 °C. Add 33% sodium hydroxide aqueous solution was added, and then dichloroacetyl chloride was slowly added dropwise into the above flask. Stirring continued for 3.5 h, the reaction mixture was then brought to room temperature, and DCM extraction yielded the crude solid, which was recrystallized with ethyl acetate to obtain compound 1.

M.p. 101.84 °C. ¹H NMR (DMSO-d₆, 500 MHz, δ: ppm), 7.74 (d, J = 1.7 Hz, 1H), 6.99 (s, 1H), 6.63 (d, J = 3.2 Hz, 1H), 6.50 (dd, J = 3.3, 1.8 Hz, 1H), 5.30 (dd, J = 9.3, 6.0 Hz, 1H), 4.13 (dd, J = 9.7, 6.0 Hz, 1H), 3.84 (t, J = 9.5 Hz, 1H), 1.55 (d, J = 3.7 Hz, 6H). MS (m/z): 299.95. Consistent with literature values.¹²

Impurity F

The mother liquor after ethyl acetate recrystallization was subjected to column chromatography to obtain a white solid impurity F.

M.p. 111.05 °C. ¹H NMR (DMSO-d₆, 500 MHz, δ: ppm), 8.66 (s, 1H), 7.61 (dd, J = 1.9, 0.8 Hz, 1H), 6.50 (s, 1H), 6.42 (dd, J = 3.2, 1.8 Hz, 1H), 6.33 (dt, J = 3.1, 0.8 Hz, 1H), 5.74 (d, J = 5.3 Hz, 1H), 4.66 (dt, J = 7.5, 5.2 Hz, 1H), 3.50 (dt, J = 13.3, 5.7 Hz, 1H), 3.42-3.28 (m, 1H). ¹³C NMR (DMSO-d₆, 125 MHz, δ: ppm), 164.24, 155.96, 142.71, 110.78, 106.80, 67.24, 65.07, 44.73. MS (m/z): 237.8. Consistent with literature values.⁴⁴

Supplemental Material

sj-doc-1-chl-10.1177_17475198241299586 – Supplemental material for Synthesis research on the herbicide safe agent Furilazole

Supplemental material, sj-doc-1-chl-10.1177_17475198241299586 for Synthesis research on the herbicide safe agent Furilazole by Yinuo Wang, Yan Liang, Yutong Li, Yue Zhang, Haiwen Song and Aibing Ke in Journal of Chemical Research

Footnotes

Author contributions

Y.N.W.: Investigation, Formal analysis, Writing—Review and Editing; Y.L.: Investigation, Formal analysis, Writing—Review and Editing; Y.T.L.: Investigation, Validation, Writing—Review and Editing; Y.Z.: Conceptualization, Methodology, Resources, Formal analysis, Writing—Review and Editing; H.W.S.: Conceptualization, Methodology, Writing—Review and Editing; A.B.K.: Conceptualization, Methodology, Formal analysis, Writing—Review and Editing.

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this paper.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Scientific Research Plan Project of Hebei Province Education Department (grant no. CXY2024049).

Ethical considerations

This article does not contain any studies with human or animal participants.

Consent to participate

All authors have agreed to participate.

Consent for publication

All authors have read the final manuscript and agreed to its publication.

Supplemental material

Supplemental material for this article is available online.

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