Metal-Free and Scalable Sulfoxide Reduction through the Couple (COCl)₂/Et₃SiH: Synthesis of Albendazole Hydrochloride

Abstract

Sulfides are valuable organic compounds and important synthetic intermediates. However, the reduction of sulfoxides to sulfides still lacks general applicability due to challenges such as harsh reaction conditions and the reliance on transition metal catalysts. Here, an extension of a previously reported metal-free reduction of sulfoxides is presented, incorporating a greener approach that, in most cases, eliminates the need for chromatographic purification. This method also enabled to scale up the reduction of albendazole to a multigram scale in excellent yield.

 

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Key words

albendazole - metal-free - reduction - sulfonium salts - sulfoxides

Organosulfur compounds are arguably among the most important functionalities in current organic chemistry.[1] Particularly, sulfides have shown exciting properties in materials science,[2] [3] as bioactive natural or synthetic compounds,[4] and in metabolic studies of sulfoxide and sulfone drugs.[5,6] Despite the prodigious variety of methodologies described in the literature to obtain sulfides, the reduction of sulfoxides is still of common interest to the synthetic community.[7] [8] Scheme [1] summarizes the general outcome of the most traditional methodologies used for this purpose: 1) Catalytic hydrogenations, which usually involve the use of transition metal complexes, and high-pressure hydrogen;[9] 2) Use of boron[10] and silicon hydrides,[11] which also need a transition metal catalyst; 3) Deoxygenations, where electrophiles are generally used to activate the sulfoxide forming a sulfonium salt, which uses a nucleophilic scavenger to afford the corresponding sulfide and the oxygenated electrophile;[12] 4) Electrochemical methods, which are believed to involve electrophilic activation and an electron transfer process that induces the loss of oxygen;[13] and 5) Photocatalytic processes, which are thought to proceed via radical fragmentation of the sulfoxide.[14] [15]

Scheme 1 Methodologies commonly used in sulfoxide reduction to sulfides

Although those methodologies are helpful, all of them still have some critical issues to solve. Notably, using homogenous metal catalysts, usually high cost, is inconvenient for large-scale preparations, in addition to the incompatibilities with other functional groups susceptible to reduction. Also, when using transition metals, there is always the risk of the product having trace metals, which is undesirable in the pharmaceutical industry.[16] On the other hand, the use of silicon and boron-based hydrides, as well as the use of electrophilic reagents, inescapably need chromatographic purification processes. Finally, most of those methodologies must be carried out at low temperatures because of the stability of the electrophilic reagents or to increase the chemoselectivity.

The reduction of sulfoxides takes on an even greater value when it leads to sulfides with outstanding biological activity. This function is present in molecules such as the benzimidazole family, with important pharmacological activities[17] principally in human and veterinary medicine to treat helminthic infections.[18] Among this family, some examples of the sulfoxide-sulfide pair of significant pharmacological interest are ricobendazole-albendazole, oxfendazole-fenbendazole and triclabendazole sulfoxide-triclabendazole (Figure [1]). Both the sulfides and the respective sulfoxides in Figure [1] (belonging to the family of benzimidazoles) present mainly anti-helminthic activity and have been studied as potential antitumor agents.[19]

Figure 1 Different bioactive couples of sulfoxide-sulfide benzimidazole for helminthic treatments

Considering that a common limitation in the pharmaceutical market of sulfoxides is chirality, sometimes this weakness can be circumvented by using the respective sulfide as a prodrug when oxidation to the respective sulfoxide takes place in vivo. Albendazole is a representative case of this behavior, undergoing rapid oxidation to chiral ricobendazole and subsequent oxidation to the respective sulfone, considered inactive.[5]

Studies of previously mentioned bioactive molecules containing the sulfide functional group are developed, especially studies focused on new activities[20] and resistance to benzimidazoles and their metabolites.[21] [22] [23] [24] [25] On this basis, several teams have studied the reduction of sulfoxides, proposing alternative methods, such as electrochemical approaches[26] or heterogeneous catalysis.[27] Unfortunately, even if the new procedures provide high chemoselectivity, the use of chromatographic purification and access to specialized equipment or catalysts are still substantial limitations. Consequently, we believe that developing new sulfoxide reduction methodologies is particularly important for the organic chemistry community. Even more so, if these methodologies are characterized by their robustness, easy purification, and treatment of the products, if they are scalable, use low-cost materials, and are performed metal-free.

In 2020, we reported a new methodology for the chemoselective reduction of sulfoxides through the combined use of oxalyl chloride and trimethoxybenzene (TMB).[28] The electrophilic reagent allows the formation of an intermediate sulfonium salt. The electrophilic chlorine is subsequently trapped by a nucleophilic, oxidizable functional group (TMB), leading to the formation of TMB-Cl in the reaction medium, as shown in Scheme [2].

Scheme 2 Sulfoxide reduction using the couple (COCl)₂/TMB

Even if this method has the most significant scope described to date, the by-product TMB-Cl is the main disadvantage of this methodology since, in some cases, it complicates the purification process of the target sulfide. On the other hand, chromatographic purification is mandatory. Based on this, we have visualized new synthetic approaches that generate a volatile by-product making the reaction attractive from a practical and economic point of view because facile purification and workup proceed with excellent yields.[29]

Herein, we describe a new approach where the sulfoxide reduction is performed by dissolving it in anhydrous DCM and adding 1.5 equivalents of triethylsilane, followed by slow addition of oxalyl chloride under an inert atmosphere (N₂). Once gas evolution has ended after adding oxalyl chloride, the starting sulfoxide has generally been completely consumed.

Table 1 Solvent Optimization

Entry	Solvent	Time (min)	Yield (%)	Purity (%)
1	Et2O	60	95	89
2	CH2Cl2	15	96	96
3	THF	180	100	87
4a	CH2Cl2	15	97	95

^a The experiment was carried out without N₂ atmosphere.

To identify the optimal solvent, we carried out the reaction in diethyl ether and THF, in addition to CH₂Cl₂, and evaluated the yields and product purity, as summarized in Table [1]. The reaction proceeded successfully in all solvents tested, even under open-vessel conditions (Table [1], entry 4). However, the best yield-to-purity ratio was achieved in CH₂Cl₂ under a nitrogen atmosphere (entry 2). If the substrate is not soluble in CH₂Cl₂, the reaction can be performed in ether solvents (entries 1 and 3), although this typically requires longer reaction times and additional purification steps.

The above procedure reduces different sulfoxides in excellent yields, generally from the evaporation at a reduced pressure of the solvent and volatile by-products of the crude reaction. Thus, ricobendazole is reduced to albendazole-HCl in 98 ± 1.5% isolated yield with a purity of 96 ± 1.0% determined by qNMR. Although the hydrochloride is of interest due to its better solubility (which increases bioavailability) than the neutral free form;[30] if neutral albendazole is needed, a simple workup with a saturated aqueous NaHCO₃ solution allows obtaining albendazole in high yields and purity (98% and 99%, respectively) as determined by qNMR. Likewise, this procedure enables various sulfides, including derivatives with alkyl substituents, aryl-aryl, and alkyl-aryl (compounds 2–12 in Figure [2]), among which chlorbenside (5) stands out as an essential sulfide with acaricidal activity obtained in quantitative yield. The important and well-known sulfoxide Omeprazole is reduced in excellent yield to the corresponding sulfide 6. It is also important to highlight some limitations. For instance, only a partial reduction is observed when strongly electron-withdrawing groups are substituting the sulfur (compound 4 in Figure [2]), probably due to the lower nucleophilicity of the sulfoxide oxygen, which leads to complex formation of the intermediate chlorosulfonium salt and, consequently, lower conversion. Nevertheless, the unreacted starting material can be quantitatively recovered without any change. Heterocyclic sulfoxides (compounds 7 and 9) were also reduced in excellent yields; however, when using sulfoxides that react via thionium ions, the yield significantly drops.[31]

Figure 2 Selected scope of sulfide products in the sulfoxide reduction through the couple (COCl)₂/Et₃SiH

We then turned our attention to evaluating the chemoselectivity of the reaction. To this end, we employed esters and aromatic iodides, which showed no reactivity under the reaction conditions; compound 10 was isolated in 94% yield. Terminal alkynes exhibited slight reactivity and compound 11 was obtained in 72% yield; however, small amounts of unidentified by-products were also observed. Finally, aldehydes proved to be fully compatible, as compound 12 was isolated in excellent yield (92%).

Finally, due to the difficulty in obtaining starting materials containing both functional groups, we conducted competition experiments to evaluate the chemoselectivity of the reaction against ketones, sulfones, and aryl bromides. In all cases, only the reduction of the sulfoxide was observed, and the competing compounds were isolated in yields exceeding 88%, demonstrating the excellent compatibility of our method with these functional groups (Scheme [3]).

Scheme 3 Competition experiments under standard conditions

Scheme 4 Mechanism proposal

On the other hand, GC-MS analysis of the crude reaction mixtures revealed the formation of Et₃SiCl (see Supporting Information) as a by-product. This observation, along with the clear formation of HCl (products 2, 6, and 7), led us to propose the reaction mechanism shown in Scheme [4]. The proposed mechanism builds upon our previously described pathway and the confirmed formation of the chlorosulfonium salt.[28] In this mechanism, hydride acts as a chloride scavenger, generating HCl. The chloride (sulfonium counterion) then behaves as a nucleophile. This increases the nucleophilicity of the Si–H bond, ultimately leading to the formation of the Et₃SiCl by-product. Further in-depth studies on the reaction mechanism are currently underway in our laboratory and will be reported in due course.

In summary, we have developed a methodology for reducing sulfoxides to sulfides through the Et₃SiH/(COCl)₂ couple. The reaction proceeds with excellent yields without metal catalysts and generally with an easy purification step (evaporation of volatiles). Additionally, it was possible to obtain albendazole hydrochloride from ricobendazole and other sulfides that demonstrate the wide scope of the reaction.

For general information, preparation of the starting materials, and physical and spectral properties of sulfides 3–12, see the Supporting Information.

 

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Methyl 5-(Propylthio)-2-benzimidazolecarbamate Hydrochloride (Albendazole-HCl, 2); Typical Procedure

To an oven-dried 250 mL round-bottom, single-necked flask (Quickfit ground-glass stopper 24/29), provided with an egg-shaped Teflon-coated stirring bar (3.5 cm) was added ricobendazole (1; 3.00 g, 10.13 mmol, 1 equiv.). Subsequently, the flask was equipped with a three-way stopcock with septa and connected through a chemically resistant hose to a vacuum/N₂ manifold line (Figure [3]A).

Figure 3 Reduction of ricobendazole (1) to albendazole-HCl (2): A) single-neck flask equipped with a three-way stopcock and connected through a chemically resistant hose to a vacuum/N₂ manifold; B) Suspension of ricobendazole connected to mineral oil bubbler leading to sodium bicarbonate solution; C) Crude after oxalyl chloride addition.

Three evacuation cycles replace the system atmosphere with N₂ (stopcock in position 1). Next, the three-way stopcock was closed (stopcock in position 3), and the connection to the manifold was replaced with a link to a mineral oil bubbler, which leads to a saturated aqueous sodium bicarbonate solution (30 mL) contained in a 50 mL Erlenmeyer flask (Figure [3]B). With the stopcock in position 2, the DCM was added through the septa (68.0 mL) in four portions via a 20 mL plastic syringe equipped with a 21-gauge stainless-steel needle. The white suspension obtained (Figure [3]B) was stirred at 250 rpm and kept at rt (20 °C). Et₃SiH (2.48 mL, 15.2 mmol, 1.5 equiv.) was added through the septum via a 5 mL plastic syringe equipped with a stainless-steel needle in a single portion. The stirring was increased to 750 rpm, and oxalyl chloride (1.35 mL, 15.2 mmol, 1.5 equiv.) was added in approximately 1 min via a 2 mL plastic syringe with a stainless-steel needle through the septa. While the addition proceeded, an intense bubbling was observed, the homogenization of the solution and progressive evolution of the reaction mixture to orange color were also observed. The color persisted when the addition was complete (Figure [3]C). Once the bubbling stopped (after approximately 50 seconds), the stopcock was guided to position 3. After 15 min of stirring at rt, TLC revealed that the starting material had been completely consumed (Figure [4]A). The elution was realized using EtOAc, R_f = 0.26 and 0.58 for ricobendazole (1) and albendazole-HCl (2), respectively; and visualized under 254 nm UV-lamp.

Figure 4 Ending of the reaction: A) TLC showing total consumption of ricobendazole (1: ricobendazole; 2: a mixture of ricobendazole + crude reaction; 3) crude reaction. B) Final aspect of the reaction.

An additional stirring for 20 min was allowed to elapse, the time during which the precipitation of the product and slight yellowing of the reaction were observed (Figure [4]B). Next, the stirring was stopped, all the connections removed, and the crude (Figure [5]A) was concentrated at reduced pressure in a rotary evaporator (500 mbar and 45 °C bath temperature). Once the solvent was removed, one portion of acetone (15.0 mL) was added, and the crude was carried out to dryness again. First, at 500 mbar and 45 °C bath temperature for 5 min, then 30 mbar and 45 °C bath temperature for 30 min. Later, one portion of CH₂Cl₂ (15.0 mL) was added, and the crude was carried out to dryness again. First, at 500 mbar and 45 °C bath temperature for 5 min, then 30 mbar and 45 °C bath temperature for 30 min. Both processes were repeated three times (this to drag all volatile by-products). After this process, the solid became much lighter and had a drier appearance (Figure [5]B). The weight of the flask revealed that 3.20 g of albendazole-HCl (2; 99% yield and 97% purity) was obtained as a stable and slightly yellow amorphous solid in good purity without additional treatment; mp 175–177 °C.

IR (ATR): 3033, 2963, 2870, 1751, 1636, 1578, 1489, 1439, 1312, 1238, 1088, 922, 756, 733, 594, 501 cm^–1.

¹H NMR (DMSO-d ₆, 400 MHz): δ = 7.55–7.59 (m, 2 H), 7.33 (dd, J = 8.4, 1.8 Hz, 1 H), 3.86 (s, 3 H), 2.93 (t, J = 7.2 Hz, 2 H), 1.56 (q, J = 7.3 Hz, 2 H), 0.96 (t, J = 7.3 Hz, 3 H).

¹³C NMR (DMSO-d ₆, 101 MHz): δ = 152.9, 144.4, 131.6, 130.7, 128.5, 125.4, 113.9, 113.4, 53.6, 35.4, 21.9, 13.1.

HRMS (ESI): m/z [M – Cl]⁺ calcd for C₁₂H₁₆N₃O₂S⁺: 266.0958; found: 266.0965.

Figure 5 Removal of volatile by-products. A) Appearance of the reaction crude after the DCM washes; B) Final appearance of albendazole-HCl.

 

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Albendazole

If neutral albendazole is needed, a simple workup with a saturated NaHCO₃ aqueous solution allows to obtain albendazole.

The albendazole-HCl (2; 3.20 g, 11.2 mmol) was poured into an Erlenmeyer containing aq NaHCO₃ (941 mg, 11.2 mmol in 34 mL of H₂O) and stirred for 6 h at rt and left in the fridge at 0 °C overnight. Then, the solid was filtered and washed with cold H₂O (26 mL). The solid was dried at 45 °C and 20 mbar for 2 h, affording 2.91 g (98% yield and 99% purity) of albendazole as a pale yellow solid; mp 205–206 °C .

IR (neat): 3005, 2958, 1620, 1558, 1442, 1265, 1091 cm^–1.

¹H NMR (DMSO-d ₆, 400 MHz): δ = 11.71 (br s, 2 H), 7.42 (s, 1 H), 7.34 (d, J = 8.2 Hz, 1 H), 7.10 (d, J = 8.2, Hz, 1 H), 3.75 (s, 3 H), 2.85 (t, J = 7.1 Hz, 2 H), 1.44–1.59 (m, 2 H), 0.94 (t, J = 7.3 Hz, 3 H).

¹³C NMR (DMSO-d ₆, 100 MHz): δ = 154.8, 147.8, 126.8, 124.1 1, 115.8, 114.2, 52.5, 36.7, 22.1, 13.1 (C=O not observed).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₇N₃O₂S⁺: 266.0958; found: 266.0965.

 

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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

C. M.-M., A. G.-T., and L. A.-C. acknowledge the Universidad de Los Andes and particularly the Chemistry Department for providing fellowships. D.G.-S. kindly recognizes the Chemistry Department of Universidad de Los Andes for logistical support.

• References

• 1 Kaiser D, Klose I, Oost R, Neuhaus J, Maulide N. Chem. Rev. 2019; 119: 8701
• 2 Poirier GE. Chem. Rev. 1997; 97: 1117
• 3 Yue TJ, Ren WM, Chen L, Gu GG, Liu Y, Lu XB. Angew. Chem. Int. Ed. 2018; 57: 12670
• 4 Wang N, Saidhareddy P, Jiang X. Nat. Prod. Rep. 2020; 37: 246
• 5 Surur AS, Schulig L, Link A. Arch. Pharm. (Weinheim) 2018; 352: 1800248
• 6 Giri P, Gupta L, Naidu S, Joshi V, Patel N, Giri S, Srinivas NR. Drug Metab. Lett. 2018; 12: 101
• 7 Li W, Chen X, Zheng T, Zou Q, Chen W. Chin. J. Org. Chem. 2019; 39: 2443
• 8 Shiri L, Kazemi M. Res. Chem. Intermed. 2017; 43: 6007
• 9 Mitsudome T, Takahashi Y, Mizugaki T, Jitsukawa K, Kaneda K. Angew. Chem. Int. Ed. 2014; 53: 8348
• 10 Yakabe S, Hirano M, Morimoto T. Synth. Commun. 2011; 41: 2251
• 11 Porwal D, Oestreich M. Synthesis 2017; 49: 4698
• 12 Jang Y, Kim KT, Jeon HB. J. Org. Chem. 2013; 78: 6328
• 13 Kong Z, Pan C, Li M, Wen K, Guo W. Green Chem. 2021; 23: 2773
• 14 Zhao J, Luo Z, Liu Y, Chenn S, He J, Xu J, Hu W, Huang Z, Xiong W. Org. Chem. Front. 2023; 10: 5254
• 15 Mo J, Han W, Liu W, Wang W, Zhao J. Chem. Asian J. 2025; 37; e202401807
• 16 Wollein U, Bauer B, Habernegg R, Schramek N. Eur. J. Pharm. Sci. 2015; 77: 100
• 17 Brishty SR, Hossain MJ, Khandaker MU, Faruque MR. I, Osman H, Rahman SM. A. Front. Pharmacol. 2021; 12: 2863
• 18 Abbas A, Newsholme W. Prescriber 2009; 20: 31
• 19 Son DS, Lee ES, Adunyah SE. Immune Netw. 2020; 20: 1
• 20 Chai JY, Jung BK, Hong SJ. Korean J. Parasitol. 2021; 59: 189
• 21 Davis CN, Winters A, Milic I, Devitt A, Cookson A, Brophy PM, Morphew RM. Sci. Rep. 2020; 10: 13445
• 22 Stuchlíková LR, Matoušková P, Vokřál I, Lamka J, Szotáková B, Sečkařová A, Dimunová D, Nguyen LT, Várady M, Skálová L. Int. J. Parasitol. Drugs Drug Resist. 2018; 8: 50
• 23 Alvarez LI, Valladares MM, Canton C, Lanusse CE, Ceballos L. Methods Mol. Biol. 2020; 2137: 213
• 24 Singh R, Bal MS, Singla LD, Kaur P. J. Parasit. Dis. 2017; 41: 463
• 25 Venturina VM, Alejandro MA, Baltazar CP, Abes NS, Mingala CN. Ann. Parasitol. 2015; 61: 283
• 26 Kong Z, Pan C, Li M, Wen L, Guo W. Green Chem. 2021; 23: 2773
• 27 Uematsu T, Ogasawara Y, Suzuki K, Yamaguchi K, Mizuno N. Catal. Sci. Technol. 2017; 7: 1912
• 28 Acosta-Guzmán P, Mahecha-Mahecha C, Gamba-Sánchez D. Chem. Eur. J. 2020; 26: 10348
• 29 Adarve-Cardona L, Gamba-Sánchez D. Processes 2022; 10: 1115
• 30 Bongioanni A, Bueno MS, Abraham-Miranda J, Chattah AK, Ayala AP, Longhi MR, Garnero C. Cryst. Growth Des. 2019; 19: 4538
• 31 Becerra-Cely L, Rueda-Espinosa J, Ojeda-Porras A, Gamba-Sánchez D. Org. Biomol. Chem. 2016; 14: 8474

Publication History

Received: 24 February 2025

Accepted after revision: 16 April 2025

Accepted Manuscript online:
16 April 2025

Article published online:
14 May 2025