Humic acid catalyzed solvent-free green protocol for synthesis of thioamide

doi:10.21203/rs.3.rs-2708761/v1

An environmentally sustainable, green synthesis of thioamide through multi-component reaction (MCR) of aldehyde, amine and sulphur catalyzed by Humic acid in solvent-free condition at 100 ^oC. The key features of this protocol are use of humic acid, a greener, easily recyclable, easily available and almost unexplored catalyst and circumvention of noxious solvents that amplify the scope of the reaction. The proposed protocol also possesses tolerance to aromatic as well as aliphatic aldehydes and amines comprising variety electron donating and withdrawing functional groups.

Humic acid

solvent-free

thioamide

multi-component reaction (MCR).

Now a days, several factors are responsible for the pollution and damage to the environment during organic synthesis such as hazardous chemicals as well as catalysts, noxious solvents and harsh reaction conditions that are tending to cause harm¹. From this understanding organic reactions should be carried out in such a way to overcome these obstacles². To construct a protocol environmentally sustainable and greener, substitution of these detrimental catalysts and solvents are desirable in drug chemistry and in organic synthesis too. As a greener alternative catalyst, biodegradable high molecular weight materials are getting noteworthy attention due to their ease of handling, low toxicity and easily separable, recoverable also reusable nature in many cases.

Among these alternates, humic acid is rarely explored polymer that has potential to manifest extraordinary catalytic activity owing to the presence of functional groups like carboxyl (-COOH) and hydroxyl (= CH-OH) in its structure (Fig. 1).

Humic acid is mostly obtained from the biodegradation of deceased organic materials available as soil, coal, peat, upland streams, dystrophic lakes and well water. From a green standpoint humic acid is non-toxic, inexpensive, easily accessible, environmentally benign, organo catalyst which is reported in very limited articles. That lead us to investigate the catalytic property of humic acid previously³. Extending its scope we further applied humic acid for preparation of thioamide in this protocol to justify its diverse nature. Additionally, the crucial disadvantage o some solvents are, their high volatility, poor recovery and pyrophoric nature. Water can be a greener substitute in organic reactions but the main disadvantage lies in hydrophobic nature of organic compounds which often results in poor yield and longer reaction time⁴. Ionic liquids are employed too as a better alternative to organic hazardous solvents but require tiresome preparations⁵. To overcome this problem we explored few solvent-free methods from the literature that has been employed successfully in organic synthesis⁶.

Thioamides are vastly used functional groups for sulfur containing natural products, heterocycles and biologically active compounds⁷ with diverse pharmacological activities such as antibacterial⁸, antioxidant⁹, antithyroid¹⁰, antiulcerative¹¹, aldose reductase inhibitor¹², antifungal¹³, antimycobacterial¹⁴, anticonvulsant¹⁵, spasmolytic¹⁶, inhibitor of estrogen receptor¹⁷ and anticancer¹⁸. Moreover, thioamides are widely applied as intermediate for synthesis of various five and six membered heterocycles like thiazolinones, thiazolins, tetrazoles, thiazoles¹⁹ and also active pharmaceutical ingredients like falostatin²⁰, fentizac²¹, fenclosic²² acid and febuxostate²³. Thioamides are also important part of drugs like ethionamide and prothionamide (antitubercular)²⁴, tolrestat (anti diabatic)¹², fimasartan (antihypertensive)²⁵. (Fig. 2)

One of the most conventional methods for synthesis of thioamide is by using Lawesson’s reagent²⁶ with amide precursor. For synthesis of thiobenzamide, benzyl chloride is also used with amine and sulfur²⁷. Other reagents like ethyl aluminium sulphide²⁸, boron sulphide²⁹, P₄S₁₀³⁰ and diethylthiocarbamoyl chloride³¹ are also used for thionation of amide. These methods have short comings like toxic nature, corrosiveness, explosive, undesirable side products along with low yield of desired product and foul smell.

A multi-component reaction (MCR) of amines, aldehydes and sulfur for synthesis of thioamide was reported by Kindler³² and is vastly applicable due to its atom economy and by-product water. Nonetheless, very limited improvements have been reported for the Kindler’s reaction using various catalysts like 4-methyl morpholine³³, p-TSA³⁴, nano-n-propyl sulphonated γ-Fe₂O₃³⁵, Na₂S. 9H₂O³⁶, montmorillonite K-10³⁷, sulphated tungsten³⁸ and sulphonic acid functionalized nano γ-Al₂O₃³⁹. Still these protocols has drawbacks like use of expensive catalysts, presence of toxic metals, harsh reaction condition, prolonged reaction time, low yield and often difficulty in product separation. Consequently to develop a greener approach to the formation of thioamide we have reported solvent-free, metal catalyst-free, robust, humic acid mediated multi-component reaction of aldehyde, amine and sulfur which is environmentally sustainable. (Scheme 1)

To sustain our progress in utilizing Humic acid as a catalyst for green synthetic methodology, we initiated our studies using benzaldehyde, pyrolodine, and sulfur as a model reaction. During optimization, we discovered that reaction time and temperature have a significant impact. The effect of temperature was evaluated at ambient, 80°C, and 100°C (Table 1). Although no yield of the desired product was observed at room temperature (Table 1, entry 7), a gradual increase in temperature up to 100°C (Table 1, entry 9) led to a notable increase in yield. We tested various solvents and a solvent-free condition. Both ethanol (Table 1, entry 1) and methanol (Table 1, entry 2) failed to produce any yield of the desired product even under reflux conditions, while water (Table 1, entry 3) and ethylene glycol (Table 1, entry 4) resulted in trace amounts of the desired product under reflux conditions and at 100°C, respectively. Under the solvent-free condition, an excellent yield of the 3-amino indole derivative was obtained within 60 minutes at 100°C (Table 1, entry 9), however, a decrease in temperature led to a reduction in the isolated yield of the product (Table 1, entries 6 and 7). As a result, none of the solvents appear to be more advantageous than the solvent-free condition, and hence, the best conditions for our Humic acid-catalyzed reaction were determined to be 100°C and solvent-free (as indicated in Table 1).

Table 1

^aOptimization of time, temperature and solvent for synthesis of thioamide.
Entry	Solvent	Temperature (^oC)	Time (min)	Yield [%]^b
1	Ethanol	Reflux	180	-
2	Methanol	Reflux	180	-
3	Water	Reflux	180	Trace
4	Ethylene glycol	100	180	Trace
5	Solvent-free	100	180	93
6	Solvent-free	80	180	72
7	Solvent-free	RT	180	46
8	Solvent-free	100	120	92
9	Solvent-free	100	60	91

The bold signifies most optimized condition.

^a Reaction of Reaction of Benzaldehyde (1 mmol), pyrolidine (1 mmol) and sulphur (1.25 mmol) in presence of Humic acid catalyst.

^b Isolated yield

Subsequently, to optimize the amount of sulfur, we commenced with a starting amount of 0.25mmol (Table 2, entry 1). However, this did not result in the desired yield. Upon increasing the amount of sulfur to 1.25mmol (Table 2, entry 4) and 1.50mmol (Table 2, entry 5), the yield of the desired thioamide also increased, though both amounts resulted in almost the same yield. Additionally, the optimal amount of catalyst loading was determined through optimization, and 15mg (Table 2, entry 7) was found to be the most suitable for our methodology (as indicated in Table 2).

Table 2

^aOptimization of amount of catalyst and amount of sulfur for synthesis of thioamide
Entry	Catalyst Loading (mg)	Sulfur (mmol)	Yield [%]^b
1	50	0.25	52
2	50	0.50	68
3	50	1.00	83
4	50	1.25	91
5	50	1.50	93
6	25	1.25	92
7	15	1.25	91

The bold signifies most optimized condition.

^a Reaction of Reaction of Benzaldehyde (1 mmol), pyrolidine (1 mmol) and sulphur (1.25 mmol) in presence of humic acid catalyst for 60 minutes.

^b Isolated yield

Later on, the efficacy of the reagents was evaluated under the optimized reaction conditions for the condensation of pyrrolidine with a diverse range of aldehydes to synthesize the target products. The reaction was found to be effective for benzaldehyde derivatives featuring a phenyl group and substituents that exhibit either electron withdrawing properties, such as nitro (Table 3, entry 3c), chloro (Table 3, entry 3d), and fluoro (Table 3, entry 3e) groups, or electron donating properties, such as methoxy (Table 3, entry 3b), hydroxy (Table 3, entry 3f), and methyl (Table 3, entry 3g) groups. Aldehydes possessing aliphatic (Table 3, entry 3k) and heterocyclic (Table 3, entry 3h, entry 3i) structures also generated moderate to high yields under the optimized reaction conditions. Furthermore, the versatility of the protocol was investigated across a wide range of amines, including those featuring pyridine (Table 3, entry 3n), benzyl (Table 3, entry 3m), alicyclic (Table 3, entry 3a to 3k), and aromatic (Table 3, entry 3o) motifs, which successfully yielded the corresponding thioamides in good yields (Table 3).

Catalyst Recovery

Subsequently, the catalyst recovery and reusability were evaluated by conducting four cycles of the reaction to synthesize phenyl(pyrrolidin-1-yl)methanethione (Table 3, entry 3a). The reaction involved the use of 1 mmol of aldehyde, 1 mmol of pyrolidine, 1.25 mmol of sulfur, and 15 mg of Humic acid in solvent-free conditions at 100°C for 60 minutes. After each run, the catalyst was easily recovered from the reaction mixture through simple filtration, followed by washing with ethyl acetate (3 × 5 mL) and drying. Although there was a slight loss in catalyst recovery and yield up to the fourth cycle, the results showed that the catalyst was almost quantitatively recovered. However, a notable decrease in both the yield and recovery of the catalyst was observed during the fifth cycle.

General Information

¹H NMR, ¹⁹F NMR and ¹³C NMR were recorded using 400 MHz, 376 MHz and 100 MHz Bruker Avance FT-NMR Spectrometer using TMS as internal standard. Splitting patterns of protons were described as s (singlet), d (doublet), t (triplet), br (broad), q (quartet) and m (multiplet).

General procedure

In our general procedure, a mixture of aldehyde (1 mmol), amine (1 mmol) and sulphur (1.25mmol) in presence of 15 mg humic acid in solvent-free condition at 100°C for 60 min in a 50 mL round-bottom flask using a magnetic stirring bar under open air for 30–60 min and the progress of the reaction was monitored on the TLC. After completion of the reaction the reaction mixture was cooled, then the solution was poured into 100 mL water and extract with ethyl acetate, washed several times with water. The combined organic mixture was dried over anhydrous Na₂SO₄, concentrated and the residue was purified by column chromatography on silica gel 60–120 mesh using petroleum ether/ethyl acetate as eluent to afford the pure product. All compounds were analyzed by NMR techniques.

In conclusion, we have established an environmentally benign, upfront and simplistic strategy for the synthesis of functionalized thioamide derivatives under solvent-free condition using humic acid without using any metal catalyst. Absence of any solvent further improves the advantage of the protocol. Catalyst can be recovered by simple filtration which makes these protocols more attractive in the field of green organic synthesis. Replacement of toxic and expensive metal catalyst by environment friendly and inexpensive humic acid is the uniqueness of this protocol which may be helpful in the medicinal as well as industrial chemistry.

Acknowledgement

GCP is thankful to University of North Bengal.

Conflicts of interests

There are no conflicts to declare.

a) Doble M, Kruthiventi AK (2007) Green Chemistry & Engineering. Academic Press 3: 53-67
b) Bryan MC, Dillon B, Hamann LG, Hughes GJ, Kopach ME, Peterson EA, Pourashraf M, Raheem I, Richardson P, Richter D, Sneddon HF (2013) Sustainable practices in medicinal chemistry: current state and future directions. J. Med. Chem. 56: 6007-6021
c) Zhang W, Cue Jr BW (2012) Green Techniques for Organic Synthesis and Medicinal Chemistry. John Wiley & Sons, Ltd.
a) Dunn P (2012) The importance of Green Chemistry in Process Research and Development. Chem. Soc. Rev. 41: 1452-1461
b) Anastas PT, Warner JC (1998) Principles of green chemistry. Green Chemistry, Theory and Practice, Oxford University Press, Oxford.
a) Mitra B, Ghosh P (2021) Humic acid: A Biodegradable Organocatalyst for Solvent-free Synthesis of Bis(indolyl)methanes, Bis(pyrazolyl)methanes, Bis-coumarins and Bis-lawsones. Chemistry Select 6: 68–81
b) Wang H, Wang Y, Han Y, Zhao W, Wang X (2020) Humic acid as an efficient and reusable catalyst for one pot three-component green synthesis of 5-substituted 1H-tetrazoles in water. RSC Adv. 10: 784-789
Breslow R (1991) Hydrophobic effects on simple organic reactions in water. Acc. Chem. Res. 24: 159–164
a) Welton T (1999) Room-Temperature Ionic Liquids. Solvents for Synthesis and Catalysis. Chem. Rev. 99: 2071–2084
b) Wasserscheid P, Keim W (2000) Ionic liquids—new solutions for transition metal catalysis. Angew Chem. Int. Ed. 39: 3772–3789
c) Gordon CM (2001) New developments in catalysis using ionic liquids. Appl. Catal. A. 222: 101–117
d) Earle MJ, Seddon KR (2000) Ionic liquids. Green solvents for the future. Pure Appl. Chem. 72: 1391–1398
Mitra B, Pariyar GC, Singha R (2017) p-TsOH mediated solvent and metal catalyst free synthesis of nitriles from aldehydes via Schmidt reaction. Tetrahedron Lett. 58: 2298–2301
a) Suzuki Y, Iwata M, Yazaki R, Kumagai N, Shibasaki M (2012) Concise enantioselective synthesis of duloxetine via direct catalytic asymmetric aldol reaction of thioamide. J. Org. Chem. 77: 4496-4500
b) Murai T, Hori F, Maruyama T (2011) Intramolecular Cyclization of in Situ Generated Adducts Formed between Thioamide Dianions and Thioformamides Leading to Generation of 5-Amino-2-thiazolines and 5-Aminothiazoles, and Their Fluorescence Properties. Org. Lett. 13: 1718-1721
c) Gopinath P, Watanabe T, Shibasaki M (2012) Studies on catalytic enantioselective total synthesis of caprazamycin B: construction of the western zone. J. Org. Chem. 77: 9260-9267
Nadeem S, Bolte M, Ahmad S, Fazeelat T, Tirmizi SA, Ahmed S, Rauf MK, Sattar SA, Siddiq S, Hameed A, Haider SZ, Fazeelat T, Tirmizi SA (2010) Synthesis, crystal structures and, antibacterial and antiproliferative activities in vitro of palladium(II) complexes of triphenylphosphine and thioamides. Inorg. Chim. Acta. 363: 3261-3269
Chernovyants MS, Aleshina NV (2012) Study on the antioxidant activity and quantification of thioamides based on nitrogen five-membered heterocycles by the kinetic technique. J. Anal. Chem. 67: 214-218
Chernovyants MS, Dolinkin AO (2010) Heteroaromatic thioamides: Structure and stability of charge transfer complexes with iodine, antithyroid activity. J. Struct. Chem. 51: 1176-1190
Gibinski K(1981) Some problems in modern anti-ulcer drug evaluation: A comparison of four gastric acid suppressors. Curr. Med. Res. Opin. 7: 516-519
Showalter HDH, Johnson JL, Werbel LM, Leopold WR, Jackson RC, Elslager EF (1984) 5-[(Aminoalkyl)amino]-substituted anthra[1,9-cd]pyrazol-6(2H)-ones as novel anticancer agents. Synthesis and biological evaluation. J. Med. Chem. 27: 253-255
Shekarchi M, Pirali-Hamedani M, Navidpour L, Adib N, Shafiee A (2008) Synthesis, antibacterial and antifungal activities of 3-aryl-5-(pyridin-3-yl)-4,5-dihydropyrazole-1-carbothioamide derivatives. J. Iran. Chem. Soc. 5: 150-158
Kunes J, Balsanek V, Pour M, Waisser K, Kaustova J (2002) On the relationship between the substitution pattern of thiobenzanilides and their antimycobacterial activity. Farm. 57: 777-782
Kulandasamy R, Adhikari AV, Stables JP (2010) Design and Synthesis of New Amides and Thioamides Derived from 3,4-Ethylenedioxythiophene as Potential Anticonvulsants. Bull. Korean Chem. Soc. 31: 3318-3326
Brunhofer G, Studenik C, Ecker GF, Erker T (2011) Synthesis, spasmolytic activity and structure–activity relationship study of a series of polypharmacological thiobenzanilides. Eur. J. Pharm. Sci. 42: 37-44;
Stauffer SR, Coletta CJ, Tedesco R, Nishiguchi G, Carlson K, Sun J, Katzenellenbogen SB, Katzenellenbogen JA (2000) Pyrazole Ligands: Structure−Affinity/Activity Relationships and Estrogen Receptor-α-Selective Agonists. J. Med. Chem. 43: 4934-4947
Hu WP, Yu HS, Chen YR, Tsai YM, Chen YK, Liao CC, Chang SN, Wang JJ (2008) Synthesis and biological evaluation of thiobenzanilides as anticancer agents. Bioorg. Med. Chem. 16: 5295-5302
a) Hisano T, Y. Yabuta Y (1973) Synthesis of Organosulfur Compounds. VIII. Cyclization Products from the Modified Willgerodt-Kindler Reaction. Chem. Pharm. Bull. 21: 511-517
b) Downer NK and Jackson YA (2004) Synthesis of benzothiazolesviaipso substitution of ortho-methoxythiobenzamides. Org. Biomol. Chem. 2: 3039–3043
c) Murai T, Hori F, Maruyama T (2011) Intramolecular Cyclization of in Situ Generated Adducts Formed between Thioamide Dianions and Thioformamides Leading to Generation of 5-Amino-2-thiazolines and 5-Aminothiazoles, and Their Fluorescence Properties. Org. Lett. 13: 1718–1721
d) Chaudhari PS, Pathare SP, Akamanchi KG (2012) o-Iodoxybenzoic Acid Mediated Oxidative Desulfurization Initiated Domino Reactions for Synthesis of Azoles. J. Org. Chem. 77: 3716–3723
e) Suzuki Y, Iwata M, Yazaki R, Kumagai N, Shibasaki M (2012) Concise Enantioselective Synthesis of Duloxetine via Direct Catalytic Asymmetric Aldol Reaction of Thioamide. J. Org. Chem. 77: 4496–4500
f) Gopinath P, Watanabe T, Shibasaki M (2012) Studies on Catalytic Enantioselective Total Synthesis of Caprazamycin B: Construction of the Western Zone. J. Org. Chem. 77: 9260–9267
Kamisuki S, Mao Q, Abu-Elheiga L, Gu Z, Kugimiya A, Kwon Y, Choo HYP (2009) A Small Molecule That Blocks Fat Synthesis By Inhibiting the Activation of SREBP. Chem. Biol. 16: 882-892
Brown K, Cater DP, Cavalla JF, Green D, Newberry RA, Wilson AB (1974) Nonsteroidal antiinflammatory agents. 1. 2,4-Diphenylthiazole-5-acetic acid and related compounds. J. Med. Chem. 17: 1177-1181
Martin S, Lenz EM, Keene W, Clench MR (2014) Identification of the Reactive Metabolites of Fenclozic Acid in Bile Duct Cannulated Rats. Anal. Chem. 86: 11281-11289
Becker MA, Kisicki J, Khosravan R, Wu J, Mulford D, Hunt B, Joseph-Ridge N (2004) Febuxostat (TMX‐67), a Novel, Non‐Purine, Selective Inhibitor of Xanthine Oxidase, Is Safe and Decreases Serum Urate in Healthy Volunteers. Nucleotides Nucleic Acids. 23: 1111-1116
a) Quemard A, Laneelle G, Lacave C (1992) Mycolic acid synthesis: a target for ethionamide in mycobacteria. Antimicrob. Agents Chemother. 36: 1316-1321
b) Wang F, Langley R, Gulten G, Dover LG, Besra GS, Jacobs WR, Sacchettini JC (2007) Mechanism of thioamide drug action against tuberculosis and leprosy. J. Exp. Med. 204: 73-78
DeMello WC, Re RN (2009) Renin angiotensin system and cardiovascular disease. Springer, New York. 1-5
Ozturk T, Ertas E, Mert O (2007) Use of Lawesson's Reagent in Organic Syntheses. Chem. Rev. 107: 5210–5278
Ozturk T, Ertas E, Mert O (2010) A Berzelius Reagent, Phosphorus Decasulfide (P₄S₁₀), in Organic Syntheses. Chem. Rev. 110: 3419–3478
Hirabayashi T, Inoune K, Yokota K, Ishii Y (1975) Insertion reactions of diethylaluminum derivatives : X. Synthesis and properties of ethylaluminum sulfide, the initial product in the reaction of triethylaluminum with hydrogen sulfide. J. Organomet. Chem. 92: 139-145
Wojtkowski PW, Dolfini JE, Kocy O, Cimarusti CM (1975) β-Thionolactam analogs of cephalosporins and penicillins. J. Am. Chem. Soc. 97: 5628-5630
Raucher S, Klein P (1981) Ultrasound in heterogeneous organic reactions. Improved procedure for the synthesis of thioamides. J. Org. Chem. 46: 3558-3559
Ogata M, Matsumoto H (1978) The Reaction of Amides with Diethylthiocarbamoyl Chloride: A New Procedure for the Preparation of Nitriles and Thioamides. Heterocycles. 11: 139-147
Kindler K, Dehn W (1921) Reduktion der Thio-amide zu primären Aminen. (Zur Kenntnis der Thioamide, II). Berichte der deutschen chemischen Gesellschaft. 54: 1080-1081
Wang F, Langley R, Gulten G, Dover LG, Besra GS, Jacobs WR Sacchettini JJC (2007) Mechanism of thioamide drug action against tuberculosis and leprosy. J. Exp. Med. 204: 73–78
Kul’ganek VV, Yanovskaya LA (1979) Wilgerodt-Kindler reaction with aromatic aldehydes. Bull. Acad. Sci. USSR Div. Chem. Sci. 28: 2402-2403
Yin Z, Zheng B (2013) Nano n-propylsulfonated magnetic γ-Fe2O3 as an efficient and reusable catalyst for the synthesis of thioamides. J. Sulfur Chem. 34: 527-531
Okamoto K, Yamamoto T, Kanbara T (2007) Efficient Synthesis of Thiobenzanilides by Willgerodt-Kindler Reaction with Base Catalysts. Synlett. 17: 2687-2690
Agnimonhan FH, Ahoussi L, Kpoviessi SDS, Gbaguidi FA, Kapanda CN, Moudachirou M Accrombessi GC (2014) Comparative study of acid and basic catalysis in microwave assistance of Willgerodt-Kindler reaction for thiobenzamides and derivatives synthesis. Int. J. Biol. Chem. Sci. 8: 386-393
Pathare SP, Chaudhari PS, Akamanchi KG (2012) o-Iodoxybenzoic Acid Mediated Oxidative Desulfurization Initiated Domino Reactions for Synthesis of Azoles. J. Org. Chem. 8: 3716-3723
Yin Z, Zheng B, Ai F (2013) Sulfonic Acid Functionalized Nano Γ-Al2O3: a New, Efficient, and Reusable Catalyst for Synthesis of Thioamides. Phosphorus, Sulfur, Silicon Relat. Elem. 188: 1412-1420

Table 3 is available in the Supplementary Files section.

Scheme 1 is available in the Supplementary Files section.

No competing interests reported.

Scheme1.png
Scheme 1. Synthesis of thioamides from aldehydes and amines
Table3.docx
GraphicalAbstractSM.docx
SupportingInformationthioamideSM.docx

Humic acid catalyzed solvent-free green protocol for synthesis of thioamide

Status:

Version 1

Abstract

Figures

Introduction

Result And Discussion

Catalyst Recovery

Material And Methods

General Information

General procedure

Conclusion

Declarations

References

Table

Scheme 1

Additional Declarations

Supplementary Files

Status:

Version 1