WO2024033677A1

WO2024033677A1 - One-pot method for the synthesis of 3-acetamido-furfural from n-acetylglucosamine

Info

Publication number: WO2024033677A1
Application number: PCT/IB2022/057408
Authority: WO
Inventors: Bruno GONÇALVES; Rafael Gomes; Carlos AFONSO
Original assignee: Faculdade De Farmácia Da Universidade De Lisboa
Priority date: 2022-08-09
Filing date: 2022-08-09
Publication date: 2024-02-15

Abstract

The object of the invention relates to a method for the synthesis of 3-acetamide-furfural of formula I by using N-acetylglucosamine as starting material. 3-Acetamide-furfural can be seen as a valuable intermediate for the production N-containing value-added chemicals. FORMULA I The one-pot method developed herein is based on the dehydration of N-acetylglucosamine in pyridine using boric acid and acid catalyst, followed by the NaIO₄ oxidative cleavage of a boronate ester intermediate, allowing the preparation of 3-acetamide-furfural in good yields. The present invention is in the technical domain of organic chemistry in particular of the preparation of a heterocyclic compound containing a furfural ring and an acetamide group directly linked to this ring in the position 3.

Description

DESCRIPTION ONE-POT METHOD FOR THE SYNTHESIS OF 3-ACETAMIDO-FURFURAL FROM N- ACETYLGLUCOSAMINE Technical field The present invention relates to a simple one-pot method for the synthesis of 3-acetamide-furfural of formula I by using N- acetylglucosamine as starting material, which can be readily obtained from renewable sources namely chitin. The compound 3- acetamide-furfural can be seen as a valuable intermediate for the production N-containing value-added chemicals.

FORMULA I The one-pot method developed herein is based on the dehydration of N-acetylglucosamine in pyridine using boric acid and acid catalyst, followed by the NaIO oxidative cleavage of a boronate ester intermediate, allowing the preparation of 3-acetamide- furfural in good yields. The process developed is a simple and handy process that does not require unconventional equipment. The present invention is in the technical domain of organic chemistry in particular of the preparation of a heterocyclic compound containing a furfural ring and an acetamide group directly linked to this ring in the position 3. Prior art Furfural is an organic compound with the formula CHO with an aldehyde group attached to the 2-position of furan. It is a colourless liquid, although commercial samples are often brown. Typically, it is a product of the dehydration of sugars, as occurs in a variety of agricultural by-products, including corncobs, oat, wheat bran, and sawdust. Furfural participates in the same kind of reactions as other aldehydes and other aromatic compounds. It exhibits less aromatic character than benzene, which can be regarded from the fact that furfural is readily hydrogenated to tetrahydrofurfuryl alcohol. When heated in the presence of acids, furfural irreversibly polymerizes, acting as a thermosetting polymer. Furfural is an important renewable, non-petroleum based, chemical feedstock. Moreover, it can be converted into a variety of solvents, polymers, fuels and other useful chemicals by a range of catalytic reduction. Hydrogenation of furfural provides furfuryl alcohol (FA), which is used to produce furan resins, that are commonly exploited in thermoset polymer matrix composites, cements, adhesives, casting resins and coatings. Further hydrogenation of furfuryl alcohol leads to tetrahydrofurfuryl alcohol (THFA), which is used as a solvent in agricultural formulations and as an adjuvant to help herbicides penetrate the leaf structure. Additional hydrogenation of

affords methyltetrahydrofuran which

an important bio-based solvent. In short, furfural is used as an intermediary to produce several other furan derivatives, such as furoic acid, via oxidation, and furan itself via palladium catalysed by vapour phase decarbonylation and due to these properties, there is a real market demanding for added-value chemicals that can be obtained from furfural. Methods for producing furfural include the

catalysed dehydration

5-carbon sugars (pentoses), particularly xylose. Typically, furan

industrially obtained by a palladium catalysed decarbonylation of furfural reaction. One of the existing methods of synthesis furan derivatives is by intramolecular cyclization of 1,4 diketone or by synthesizes with beta-ketone acid (ester) and alpha-halogenated ketone as starting materials. However, these reactions, besides specific reactants need a transition metal as catalyst and is a multi-step reaction. Document CN105175368 discloses a method for preparation of 3- furfural compounds using a palladium catalyst, a heteropoly acid catalyst and a Lewis acid catalyst solution and adding alpha, beta-unsaturated carboxylic ester and aliphatic aldehydes with a final step of separation and extraction of 3-furoic acid esters by addition of an extraction agent. However, this document does not disclose the 3-acetamide-furfural. Moreover, it discloses a multi- step reaction with a palladium catalyst. Additionally, these furans are not prepared from biorenewable resources, thus contributing less to sustainability, neither contain sustainable nitrogen, a major feature of 3-acetamido-furfural derived from N- acetylglucosamine. Another document, Cornelis van der Loo et al. (The dehydration of N-acetylglucosamine (GlcNAc) to enantiopure dihydroxyethyl acetamidofuran (Di-HAF). Org. Biomol. Chem., 2021, 19, 10105- 10111) discloses synthesis of enantiopure dihydroxyethyl acetamidofuran (Di-HAF) by dehydratation of GlcNAc in pyridine in the presence of phenylboronic acid and triflic acid. However, only the substituted furan derivates 5-(hydroxymethyl)furfural (5-HMF), 3-acetamido-5-acetylfuran (3A5AF) and dihydroxyethyl acetamidofuran (Di-HAF) are disclosed. Further, this document is focused on the Di-HAF compound since it presents unique chiral characteristics in comparison to the other known 3-acetamido-furan derivatives. The method herein discloses a combination of phenylboronic acid and Bronstead acids is used, in particular the triflic acid to dehydrate the N-acetylglucosamine (GlcNAc) providing a more stable boronate ester than using boric acid that prevents the third elimination step to 3A5AF. The extraction and purification of the intended compound, dihydroxyethyl acetamidofuran (Di-HAF) needs to be performed in a silica suspension, then filtration with silica patches and several washed several times with different alcohols followed by concentration of the residue in vacuum. This method is time spending, involves several steps and complex reactants. Additionally, despite the importance of Di-HAF, the diol moiety vs aldehyde present in 3-acetamide-furfural render the furan inert towards several reaction conditions utilized for the formation of high value chemicals from furfural/5-HMF. Moreover, this document teaches away the use of boronic acid followed by oxidation, which it is mentioned as a non-working embodiment. Therefore, there is a need to fulfil the demand of science and market for new nitrogen-containing platforms that could be used as starting material for the synthesis of more complex N-containing value-added chemicals, in which the 3-acetamide-furfural fulfil those requirements. To solve the prior art problems, the present invention proposes a new method of producing unreported 3-acetamide-furfural based on the dehydration of N-acetylglucosamine in pyridine using boric acid and acid catalyst, followed by the NaIO oxidative cleavage of a boronate ester intermediate, allowing the preparation of 3- acetamide-furfural in good yields. This is a one-pot method that is simple and handy and does not require unconventional equipment. Description of a preferred embodiment The present invention relates to a simple one-pot method for the synthesis of 3-acetamide-furfural of formula I by using N- acetylglucosamine as starting material. The compound 3-acetamide- furfural can be used as a valuable intermediate for the production N-containing value-added chemicals.

FORMULA I N-acetylglucosamine can be readily obtained via depolymerization of chitin, the second most abundant biopolymer in nature and that can be obtained in high quantities from seafood waste. Due to its naturally fixed nitrogen atom, N-acetylglucosamine represents an excellent starting material for the preparation of nitrogen- containing molecules. Accordingly, the method of the present invention starts by providing the diol dihydroxyethyl acetamidofuran (Di-HAF) from N- acetylglucosamine as described in prior art (Org. Biomol. Chem., 2021, 19, 10105-10111). Considering the presence of a vicinal diol moiety, Di-HAF is dissolved in a mixture of THF/water and treated with sodium periodate (NaIO). The treatment with NaIO succeeds in promoting the oxidative cleavage of the vicinal diol into an aldehyde group. The aldehyde compound thus obtained can be purified by column chromatography affording a pure 3-acetamide-furfural compound in 76% yield. This process allows the preparation of 3-acetamide-furfural in two synthetic and purification steps, as shown in the scheme 1 below: Scheme 1

A) PhB(OH)2 (1.5 eq.), TfOH (1 eq.), Pyridine, 116 °C, 30 min, Mol. Sieves (4 Å),(Org. Biomol. Chem., 2021, 19, 10105-10111); B) THF/H2O, NaIO4 (1.5 eq.), RT, 2h, 76 % Yield To the best of our knowledge, new 3-acetamide-furfural as not been described in prior art and is an excellent starting point for developing new bulk commodity and fine chemicals. With the goal of developing a simpler methodology, the NaIO oxidative cleavage of the phenylboronic ester intermediate in the reaction solvent, pyridine, was accessed. This would provide the desired compound 3-acetamide-furfural, in a one-pot method (Scheme 2). Thus, N-acetyl glucosamine is dissolved in pyridine and treated with phenylboronic acid and trifluoromethanesulfonic acid at 116 ºC for 30 min. After cooled down to room temperature (20 to 25ºC), NaIO and water (4:1 pyridine/water) are added to the reaction mixture, and the reaction proceed at room temperature for 1 hour. After completion of the reaction the solvent is removed at reduced pressure affording an oily crude, as shown in Scheme 2 below. A simple purification by column chromatography of silica with ethyl acetate or similar as eluent confirmed the preparation of 3- acetamide-furfural with 85% yield. In one embodiment of the present invention N-acetyl glucosamine is derived from chitin. In another embodiment, N-acetyl glucosamine is derived from chitosan. In another embodiment, N-acetyl glucosamine is derived from glucosamine. In another embodiment, chitin is used directly instead of N-acetyl glucosamine. Scheme 2.

A) PhB(OH)2 (1.5 eq.), TfOH (1 eq.) Pyridine, 116 °C, 30 min, Mol. Sieves (4 Å)(Org. Biomol. Chem., 2021, 19, 10105-10111); B) then NaIO4 (1.5 eq.), water, RT, 85% yield. In the original method for the preparation of Di-HAF, the use of phenylboronic acid instead of the much cheaper boric acid, was justified by the labile nature of the boronate ester formed by boric acid. It was postulated that this labile nature favors the in situ hydrolysis of the boronate ester, releasing the diol, which could rapidly suffer an elimination step to form a ketone. To investigate if boric acid can be employed in our one-pot process, N-acetyl glucosamine was dissolved in pyridine and treated with boric acid and trifluoromethanesulfonic acid at 116ºC for 30 min. After cooled down to room temperature, NaIO and water (4:1 pyridine/water) are added to the reaction mixture, and the reaction proceed at room temperature for 1 hour. After completion of the reaction the solvent was removed at reduced pressure affording an oily crude. After isolation and purification by column chromatography, surprisingly it was observed that in contrast with the previously hypothesized dehydration to 3A5AF, 3- acetamide-furfural was successfully prepared in 92 % yield, as shown in scheme 3. Scheme 3.

A) B(OH)3 (1.5 eq.), TfOH (1 eq.) Pyridine, 116 °C, 30 min, Mol. Sieves (4 Å) B) then NaIO4 (1.5 eq.), water, RT, 92% yield. To investigate the scope of acid catalysts which can promote the reaction, a series of combinations of Boric acid and alternative Brønsted-acids were performed, namely the Acetic acid, the p- toluenesulphonic acid, the Sulfuric acid and the Trifluoromethanesulfonic acid all at 1 eq. The toluenesulphonic acid presented the best results. Therefore, in one embodiment of the present invention, the acid catalyst is a Brønsted-acid. In another embodiment, the acid catalyst is Acetic acid, the p- toluenesulphonic acid, the Sulfuric acid and the Trifluoromethanesulfonic acid or combinations thereof. In a preferred embodiment, the acid catalyst is Trifluoromethanesulfonic acid. N-acetyl glucosamine (100mg) was dissolved in pyridine and treated with boric acid and Brønstead-acid at 116ºC for 30 min. After cooled down to room temperature, NaIO and water (4:1 pyridine/water) were added to the reaction mixture, and the reaction proceeded at room temperature for 1 hour. After completion of the reaction the solvent can be removed at reduced pressure affording an oil crude, which was isolated and purified by column chromatography to afford the desired product. All the acid catalyst tested promoted the obtention of 3-acetamide- furfural, however the higher yield was clearly obtained with trifluoromethanesulfonic acid, as shown in Table 1. Table 1. Effect of the acid catalyst in the yield of 3- acetamide-furfural Acid catalyst (1 eq) Yield (%) Acetic acid 26 % p-toluenesulphonic acid 50 % Sulfuric acid 47 % Trifluoromethanesulfonic acid 93 % The influence of the quantity of acid catalyst on the success and yield of the process, was also assessed. Trifluoromethanesulfonic acid was the acid catalyst selected and the same reaction conditions were employed. Similar yields were obtained using 1 or 0.5 equivalents of acid catalyst. Lower quantities of acid catalyst reduced significantly the yield of the reaction. Thus, the method allows the reduction in half of the quantity acid catalyst needed without compromise the yield of the reaction in comparison with previously reported dehydrations of N-acetyl- glucosamine, as shown in Table 2. Table 2. Effect of amount of acid catalyst in the yield of 3- acetamide-furfural Acid catalyst quantity Yield (%) (eq.) 1 93 % 0.5 94 % 0.4 81 % 0.2 50 % 0.1 52 % The scalability of the method of the invention to gram scale was also demonstrated, by treating 2 grams of N-acetylglucosamine dissolved in pyridine with boric acid and trifluoromethanesulfonic acid at 116°C for 30 min. Water (in the proportion of pyridine/water 4:1) and NaIO (1.5 eq.) are added to the reaction mixture and allowed to cool down to room temperature (20-25ºC). The reaction proceeds by stirring at room temperature for 1 h 30 min. After purification flash column chromatography 3-Acetamide- furfural can be obtained with 76 % yield., as shown in scheme 4. Scheme 4.

A) B(OH)3 (1.5 eq.), TfOH (1 eq.) Pyridine, 116 °C, 30 min, Mol. Sieves (4 Å) B) then NaIO4 (1.5 eq.), water, RT, 76% yield. In conclusion, - The oxidative cleavage of Di-HAF yields a novel 3-acetamide furfural, containing an aldehyde moiety that can be chemically explored. - Trapping the boronic ester with the oxidating agent allows the use of cheap boric acid instead of boronic acids in a one-pot process, herein potentiating the chemical reaction efficiency by avoiding separation and purification of intermediates, thus saving time and resources. - The dehydration-isomerization of N-acetylglucosamine (GlcNAc) to 3-acetamide furfural is catalyzed by Brønsted-acids being trifluoromethanesulfonic acid the most efficient. - Additionally, it has been shown that the quantity of acid catalyst (trifluoromethanesulfonic acid) employed during the dehydration of N-acetylglucosamine step could be reduced in half without affecting the yield of the process. - The 3-acetamide-furural could be isolated and purified using a simple column chromatography procedure. - The process developed herein is a simple and handy process that does not require unconventional equipment, thus can be followed by everyone. - Alternatively, the process for the preparation of 3- acetamide-furural can also be carried out in two steps by isolation of a diol intermediate compound, which is treated with sodium periodate in THF/water. - Finally, the one-pot process of the present invention enables the production of 3-acetamide-furfural at gram scale. Examples Example 1. Preparation of 3-actetamide-furfural with Di-HAF The diol dihydroxyethyl acetamidofuran (Di-HAF) was prepared from N-acetylglucosamine according to the described in the prior art (Org. Biomol. Chem., 2021, 19, 10105-10111). Then, Di-HAF (718 mg) was dissolved in a mixture of THF/water (4:1) and treated with 1.5 eq. of sodium periodate (NaIO). The aldehyde compound thus obtained was purified by column chromatography of silica length = 28 cm, internal diameter = 2 cm, eluent = ethyl acetate (1 L)) affording a pure 3-acetamide- furfural compound in 76% yield (454 mg), as shown in Scheme 1 presented in the Description. Example 2. Effect of oxidative cleavage of the phenylborate ester by NaIO in the preparation of 3-actetamide-furfural N-acetyl glucosamine (100mg) was dissolved in pyridine and treated with phenylboronic acid (1.5 eq.) and trifluoromethanesulfonic acid (1.eq) at 116ºC for 30 min. After cooled down to room temperature, NaIO (1.5 eq) and water (4:1 pyridine/water) were added to the reaction mixture, and the reaction proceeded at room temperature for 1 hour. After completion of the reaction the solvent was removed at reduced pressure in a rotaevaporator (pressure = 200 mb, water batch temperature = 40 ºC)) affording an oily crude. A simple purification by column chromatography of silica (as described in example 1) confirmed the preparation of 3acetamide-furfural with 85% yield, as showed in Scheme 2 in the Description. Example 3. Effect of boric acid in the preparation of 3- actetamide-furfural N-acetyl glucosamine (100mg) was dissolved in pyridine and treated with boric acid (1.5 eq.) and trifluoromethanesulfonic acid (1.eq) at 116ºC for 30 min. After cooled down to room temperature (20- 25ºC), NaIO (1.5 eq.) and water (4:1 pyridine/water) were added to the reaction mixture. The reaction proceeded at room temperature for 1 hour. After completion of the reaction the solvent was removed at reduced pressure as described in example 2 affording an oily crude. After isolation and purification by column chromatography of silica (as described in example 1), surprisingly it was observed that 3-acetamide-furfural was successfully prepared in 92% yield, according to Scheme 3 in the Description. Example 4. Effect of trifluoromethanesulfonic acid in the yield of 3-acetamide-furfural Several of combinations of Boric acid and alternative Brønstead- acids were performed: N-acetyl glucosamine (100mg) was dissolved in pyridine and treated with boric acid (1.5 eq.) and Brønstead- acid (1.eq) at 116ºC for 30 min. After cooled down to room temperature, NaIO (1.5 eq.) and water (4:1 pyridine/water) were added to the reaction mixture, and the reaction proceeded at room temperature for 1 hour. After completion of the reaction the solvent was removed at reduced pressure affording an oil crude, which was isolated and purified by column chromatography to afford the desired product. All the acid catalyst tested promoted the obtention of 3-acetamide-furfural, however the higher yield was clearly obtained with trifluoromethanesulfonic acid as shown in Table 1. Table 1. Effect of the acid catalyst in the yield of 3-acetamide- furfural Acid catalyst (1 eq) Yield (%) Acetic acid 26 % p-toluenesulphonic acid 50 % Sulfuric acid 47 % Trifluoromethanesulfonic acid 93 % Example 5. Effect of the amount of acid catalyst in the yield of 3-acetamide-furfural The influence of the quantity of acid catalyst on the success and yield of the process, was also investigated. Trifluoromethanesulfonic acid was the acid catalyst selected and the same reaction conditions were employed. Similar yields were obtained using 1 or 0.5 equivalents of acid catalyst. Lower quantities of acid catalyst reduced significantly the yield of the reaction. Thus, our method allowed the reduction in half of the quantity acid catalyst needed without compromise the yield of the reaction as shown in Table 2. Table 2. Effect of the amount of acid catalyst in the yield of 3- acetamide-furfural Acid catalyst quantity Yield (%) (eq.) 1 93 % 0.5 94 % 0.4 81 % 0.2 50 % 0.1 52 % Example 6. Potential scaling-up of the process to produce 3- acetamide-furfural The scalability of our method to gram scale was also demonstrated, by treating N-acetylglucosamine (2000 mg) dissolved in pyridine (0.2 M), with boric acid (1.5 eq.) and trifluoromethanesulfonic acid (1 eq.) at 116 °C for 30 min. Water (in the proportion of pyridine/water 4:1) and NaIO (1.5 eq.) were added to the reaction mixture it cooled down to room temperature and the reaction proceed by stirring at room temperature for 1 h 30 min. After purification flash column chromatography of silica (as described in example 1) 3-Acetamide-furfural was obtained with 76 % yield, according to scheme 4 in the Description.

Claims

CLAIMS 1. A one-step process for preparing 3-acetamide-furfural from N- acetylglucosamine comprising the reaction of N- acetylglucosamine with boronic acid or boric acid (0.1 - 2 equiv.) in the presence of a Brønsted acid catalyst in pyridine at a temperature between 100 – 140ºC, followed by the treatment with sodium periodate (>1 equivalent) at temperature from 15 to 30 ºC.

2. A process, according to claim 1, wherein the acid catalyst is selected from is Acetic acid, the p-toluenesulphonic acid, the Sulfuric acid and the Trifluoromethanesulfonic acid or combinations thereof.

3. A process, according to claim 2, wherein the acid catalyst is the trifluoromethanesulfonic acid (0.1 - 1 equiv.).

4. A process, according to claim or 3, wherein the amount of acid catalyst is reduced in half (0.5 equiv).

5. A process according to claim 1, where the dihydroxyethyl acetamidofuran (Di-HAF) is reacted with sodium periodate (>1 equiv) in a mixture of THF/HO.

6. A process according to any of the claims 1 to 5, wherein there is a further step of purification of the resulting crude oil of the process by column chromatography of silica with ethyl acetate as eluent confirmed the preparation of 3-acetamide- furfural with 85% yield.

7. A process according to any of the claims 1 to 6 where N-acetyl glucosamine is derived from chitin.

8. A process according to any of the claims 1 to 6 where N-acetyl glucosamine is derived from chitosan.

9. A process according to any of the claims 1 to 6 where N-acetyl glucosamine is derived from glucosamine.

10. A process according to any of the claims 1 to 6 where chitin is used directly instead of N-acetyl glucosamine.

11. A heterocyclic compound comprising a furfural ring and an acetamide group directly linked to this ring in the position 3 for use in intermediary chemical reactions, said compound being the thus defining the compound 3-Acetamide-furfural of formula I.

Formula I