Isoselenocyanates: Synthesis and Their Use for Preparing Selenium-Based Heterocycles

Abstract

Isoselenocyanates (ISCs) are a class of organoselenium compounds that have been recognized as potential chemotherapeutic and chemopreventative agents against cancer(s) and infectious diseases. ISC compounds are chemically analogous to their isosteric relatives, isothiocyanates (ITCs); however, they possess increased biological activity, such as enhanced cytotoxicity against cancer cells. ISCs not only serve as significant products, but also as precursors and essential intermediates for a variety of organoselenium compounds, such as selenium-containing heterocycles, which are biologically active. While syntheses of ISCs have become less difficult to accomplish, the syntheses of selenium-containing heterocycles are often difficult due to the use of highly toxic selenium reagents. Because of this, ISCs can serve as versatile reagents for the preparation of these heterocycles. In this review, the classical and recent syntheses of ISCs will be discussed, along with notable and recent synthetic work employing ISCs to access novel selenium-containing heterocycles.

Graphical Abstract

1. Introduction

Selenium, like the moon, has been described to have two faces, as it is both toxic and essential to organisms.¹ Early studies first recognized the role of selenium as a toxin. This recognition came from investigating the cause of ‘alkali disease’ and ‘blind staggers’, which are livestock diseases in the American West and the Plains states. Both diseases were forms of selenosis due to the ingestion of cereal crops, animal forage and Astragalus (or better known as ‘locoweed’), in all of which were found high doses of selenium due to the selenium-rich soils.^2–5 This investigation concluded that selenium ‘is in a compound very similar to cysteine.’⁶ However, this was not widely recognized as it predated the discovery of selenocysteine by 40 years.⁷ As research into selenium advanced, its importance and necessity expanded.

Selenium is known as an essential trace element in the nutrition of both animals and humans. It is naturally present in many foods, added to others, and is readily available as a dietary supplement. Selenium has been deemed nutritionally essential for humans and is a constituent of selenoproteins that participate in critical roles such as reproduction, thyroid hormone metabolism, DNA synthesis and protection from oxidative damage and infection.⁸ Selenium exists in two forms: inorganic (such as selenate and selenite) and organic (such as selenocysteine and selenomethionine) (Figure 1).⁹ Most selenium is in the form of selenomethionine in animal and human tissues where it can be integrated nonspecifically with methionine.

Figure 1.

Inorganic and organic forms of selenium

A major site of selenium storage is found in the skeletal muscle where 28–46% of the total selenium collection dwells.¹⁰ Major food sources of selenium are Brazilian nuts, seafoods, and organ meats.⁸ Other food sources include meats, cereals and other grains, and dairy products. In the American diet, major food sources of selenium are breads, grains, meat, poultry, fish and eggs.¹¹ For humans, the concentration dependance of selenium can be both beneficial and detrimental. Dietary levels depend on age, but after the age of 14 the recommended selenium intake is 55 μg/day, which is known to prevent the development of various cancers. A high selenium intake, such as >350 μg/day, can be carcinogenic, genotoxic, and cytotoxic.^12–14

1.1. Selenium and Health

The chemopreventative effects of daily selenium intake are often attributed to the ability of seleno compounds to function as an antioxidant and control the redox status of cells, ultimately protecting against oxidative stress. In contrast, the effects of high selenium intake enable the seleno compounds to become redox active, pro-oxidative, and cytotoxic to tumor cells which contain increased levels of reactive oxygen species (ROS), but can also be toxic towards healthy cells.¹⁵

Outside of its recognized position in enzymes, such as selenocysteine, selenium and selenium compounds have been found to inhibit tumorigenesis in a range of animal models. Studies have shown that selenium can be used as a supplemental agent to help reduce the risk of cancer. In vivo chemical and viral carcinogenesis studies show a reduced prevalence of tumors following selenium supplementation.¹⁶ Organoselenium compounds have been shown to hinder the initiation and post-initiation phases of chemical carcinogenesis, as well as displaying antitumorigenic, anti-angiogenic and pro-oxidant activity in cancer cells.^16–18 Despite the complex and ambiguous mechanisms of action, organoselenium compounds are proposed to induce DNA damage, regulate the cell cycle, inhibit cellular growth, induce apoptosis and generate ROS.^16–19 Furthermore, it has been reported that patients with melanoma, breast cancer, and pancreatic cancer have exhibited decreased selenium levels in whole blood or serum compared to healthy controls.²⁰

In spite of the abovementioned importance of selenium and organoselenium compounds, there is evidence showing contradictory antioxidant behaviors in selenium-containing compounds, suggesting that these compounds must be examined individually for their antioxidant abilities. For example, selenium-based agents have been recognized as redox modulators for activity in redox catalysts, intracellular redox control and apoptosis, but specificity is in question. The initial redox targets of these agents are unknown. Such targets can include redox-sensitive cysteine-containing Bcl proteins, which control apoptosis at early stages. However, certain caspases can also be targeted, due to redox sensitivity, which targets apoptosis mechanisms at later stages. On the other hand, the selenium redox modulators may not just be targeting a specific target, but rather cause a wide-ranging shift in intracellular redox states, which results in widespread modification of proteins and enzymes.²¹ Because of this, there are contradictory literature reports of the efficacy of selenium, but it would be unwise to ignore the therapeutic potential in the field of selenium chemistry.

The most important drug candidates containing selenium are 2-(α-hydroxy-β-N-piperidine-ethyl)selenophene and related anti-arrhythmic agents,²² selenophene-containing inhibitors of type IIA bacterial topoisomerases,²³ 4′-seleno-nucleosides as next-generation nucleosides,²⁴ and the anti-melanoma drug PBISe [S,S′−1,4-phenylenebis(1,2-ethanediyl)bis-isoselenourea] (Figure 2).²⁵

Figure 2.

Se-containing therapeutically active compounds: PBISe and ebselen

Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), which was first synthesized in 1924,²⁶ is a synthetic organoselenium drug with anti-inflammatory, anti-oxidant and cytoprotective activity (Figure 2). It is currently being considered as a potential treatment for severe COVID-19 cases.²⁷

2. Isoselenocyanates

ISCs have been recognized as potential chemotherapeutic and chemopreventative agents. In particular, ISCs have activity against melanoma,^20,28 lung cancer,^29,30 colon cancer,^31,32 liver cancer,²⁰ breast cancer^33,34 and prostate cancer.³⁵ However, the applications of these agents are not limited to cancers as they have activity against parasitic leishmaniasis³⁶ and infectious diseases such as malaria and tuberculosis.³⁷ Chemically, ISCs are similar to their isosteric relatives: isothiocyanates (ITCs). While the chemistry of ISCs is not as established when compared to ITCs, ISCs are still of huge importance based on the classic observation that selenium compounds have increased activity in cancer deterrence than their sulfur analogues.³⁸ Structure–activity relationship (SAR) studies comparing ITC and ISC analogues reveal ISCs to be more cytotoxic towards cancer cells.²⁰ Chemically, ISCs can serve as precursors and essential intermediates for a variety of organoselenium compounds, such as selenocarbamates, heterocycles, and selenoureas, all of which are biologically active.

2.1. Preparation of Isoselenocyanates

There are multiple synthetic pathways to access isoselenocyanates (Scheme 1). Classically, organic ISCs are synthesized by the addition of elemental selenium to isocyanides (Scheme 1, eq. 1).³⁹ While this method provides moderate to high yields while using inexpensive elemental selenium, major disadvantages are the varied toxicities and extremely pungent odor of isocyanide molecules.^40,41 ISCs have also been synthesized by using a primary amine, CSe₂ and HgCl₂ in the presence of triethylamine (eq. 2).⁴² This method attempts to stray away from isocyanides. However, while this method does produce ISCs, there is an additional amine-mercuric chloride adduct which leads to the formation of undesired side products such as selenourea, carbodiimide or (ironically) isocyanides.⁴³ Ultimately, isolation and purification of the desired product becomes difficult. Other methods with notable limitations include the reaction of isocyanates with phosphorous(V) selenide (eq. 3),⁴⁴ the reaction of sodium selenide with N-arylcarbonimidic dichlorides (eq. 4),⁴⁴ a photochemical rearrangement of selenocyanates (eq. 5),⁴⁵ and the in situ formation of ISCs via a one-pot cycloaddition by reacting nitrile oxides with primary selenoamides, which can further react with amines to form selenoureas (eq. 6).⁴⁶ Along with ISCs, acyl-isoselenocyanates (acyl-ISCs) are also easily synthesized from acyl chlorides and potassium selenocyanate (KSeCN) in acetone (eq. 7).^40,47 Imidoyl ISCs are also prepared in a similar manner with the exception of using imidoyl chloride as the starting material (eq. 8).⁴⁸

Scheme 1.

Various synthetic approaches to prepare ISCs

It was Barton et al. who developed the first convenient, one-pot procedure for the preparation of ISCs with high yields (eq. 9).³⁹ This method provided ISCs from their corresponding formamides in toluene while in the presence of phosgene, triethylamine and elemental selenium. The formamides are subject to dehydration using phosgene and triethylamine, leading to the in situ isocyanide which is ‘immediately consumed upon generation’ by the elemental selenium to give the ISCs.³⁹ This one-pot procedure became key to begin accessing ISCs. However, due to the high boiling point of toluene, the polymerization of intermediates was observed. A similar protocol uses the synthetic method of Barton et al., however, the solvent was changed to petroleum ether and bis(trichloromethyl)carbonate (triphosgene) was used, a ‘safer’⁴⁹ reagent when compared to phosgene.⁵⁰ This reaction occurs between formamides and bis(trichloromethyl)carbonate while in the presence of triethylamine and elemental selenium (eq. 10).⁵⁰ Another modification still uses triphosgene, instead of the highly toxic phosgene reagent, but the solvent is changed to dichloromethane in order to lower the reflux temperature and leads to less polymerization of intermediates (eq. 11).⁵¹ Additionally, rather than reacting the formamides in the presence of all the reagents, this method allows for the generation of the corresponding isocyanide without interruption and minus the presence of selenium. Once the isocyanide intermediate is observed, via TLC and at times via a pungent odor, elemental selenium is added and the desired ISC product is generated under reflux. These ‘simple’ modifications have been shown to successfully lead to the synthesis of previously prepared ISCs as well as novel phenyl/alkyl ISCs, aryl ISCs and sugar-derived ISCs in decent yields.^51,52 A recent method for ISC synthesis was reported by Zakrzewski et al. involving a biphasic aqueous/organic system functioning under strongly alkaline conditions (eqs. 12 and 13). This unique method allows the formation of ISCs directly from the corresponding amines or isocyanides under phase-transfer conditions in a biphasic 50% aqueous NaOH/dichloromethane solvent system by utilizing the phase-transfer catalyst Aliquat 336.⁵³ This method provides an effective route for synthesizing ISCs with comparative yields. However, the timely addition of elemental selenium is crucial in this reaction. When starting from an amine, the addition of selenium should be done after the complete in situ conversion of the amine into the isocyanide, otherwise a nucleophilic amine and electrophilic isoselenocyanate will be present simultaneously, leading to the formation of selenoureas [(RNH)₂C=Se] as major side products.⁵³

Accessing ISCs has been made possible, however, it is important to note that simpler and safer methods to synthesize ISCs must be, and are still being, developed. Although these ISC molecules can be useful, stability can be an issue. For example, some ISCs are sensitive to light and can undergo decomposition regressing to pungent isocyanides and elemental selenium.⁵³ Nevertheless, ISCs, as organoselenium compounds, are still useful starting materials, intermediates and products, and are promising in the field of medicinal chemistry.

3. Selenium-Containing Heterocycles

Because many organic derivatives of selenium have been shown to have biological activity, selenium-containing heterocycles are of major interest because of their chemical properties and potential biological activities. Unfortunately, syntheses of selenium-containing heterocycles involve the use of toxic selenium reagents, which are often difficult to handle and store. For this reason, synthetic approaches using easily accessible, stable and less toxic selenium reagents are required. Thus, ISCs can be used as highly versatile synthons for the preparation of selenium-containing heterocycles.

3.1. Notable Synthetic Work

Garud et al. reported the first regioselective iodocyclization of O-allyl selenocarbamates.⁵⁴ These O-allyl selenocarbamates were synthesized from phenyl-ISC and substituted allyl alcohols in THF in the presence of NaH. The formed O-allyl selenocarbamates were then subjected to iodocyclization using either I₂ or N-iodosuccinimide (NIS) as the electrophile. This led to 4-alkyl-2-imino-1,3-oxoselenolanes, treatment of which with DBU gave (Z)- or (E)-4-alkylidene-2-imino-1,3-oxaselenolanes (Scheme 2).

Scheme 2.

Regioselective iodocyclization of O-allyl selenocarbamates

Fleischhauer et al. reported an efficient entry to novel highly substituted 1,3,4-selenadiazines. This was accomplished by cyclizing bis-arylimidoyl chlorides of oxalic acid via hydrazinolysis to yield Δ²-1,2-diazetines. These highly strained and highly reactive rings react readily with ISCs and acyl-ISCs to yield highly substituted 1,3,4-selenadiazines (Scheme 3).⁵⁵

Scheme 3.

Synthesis of highly substituted 1,3,4-selenadiazines

Zhou et al. presented a new modification of the Leibscher–Hartmann synthesis of 1,3-selenazoles using N-(N-phenylimidoyl)selenoureas, which are prepared from stable N-phenylimidoyl isoselenocyanates. Treatment of these N-phenylimidoyl isoselenocyanates (prepared from benzamide derivatives) with amines afforded (N-phenylimidoyl)selenourea derivatives. Subsequent addition of activated bromoethylene compounds followed by a base yielded 2,4,5-trisubsituted-1,3-selenazoles (Scheme 4).⁵⁶

Scheme 4.

Synthesis of 2,4,5-trisubsituted-1,3-selenazoles

Koketsu et al. showed that treatment of substituted acryloyl isoselenocyanates (generated in situ from acryloyl chlorides and potassium selenocyanate) with sodium hydrogen selenide (NaSeH) afforded 2-selenoxoperhydro-1,3-selenazin-4-ones in good to moderate yields (Scheme 5).⁵⁷

Scheme 5.

Synthesis of 2-selenoxoperhydro-1,3-selenazin-4-ones

Toyoda and Koketsu have reported a clever synthesis of selenium- and sulfur-containing 2-imino-1,3-thiaselenolane heterocycles. This was achieved by reacting isoselenocyanates with allyl mercaptan to afford S-allyl-selenocarbamates in relatively short reaction times (10–30 minutes). Next, smooth transformations into 2-imino-1,3-thiaselenolanes, as Z/E mixtures at the imine position, were accomplished via iodocyclization. It is important to note that the overall yield diminished in the presence of an EWG attached to the ISC, however, only one entry contained an EWG (4-chlorophenyl-ISC) (Scheme 6).⁵⁸

Scheme 6.

Synthesis of 2-imino-1,3-thiaselenolanes

3.2. Recent Synthetic Work

3.2.1. Synthesis of N-(3-Methyl-4-phenyl-3H-selenazol-2-ylidene)benzamide Derivatives

In a paper published in 2018, Singh et al. looked to develop a novel and efficient one-pot, three-component synthesis of N-(3-methyl-4-phenyl-3H-selenazol-2-ylidene)-benzamide derivatives using readily available starting materials: aroyl isoselenocyanates, phenacyl bromide and methylamine.⁵⁹ This particular synthesis is relatively simple and provides an elegant route to access potential therapeutic organoselenium compounds (Scheme 7).

Scheme 7.

Synthesis of N-(3-methyl-4-phenyl-3H-selenazol-2-ylidene)benzamide derivatives

A solution of aroyl isoselenocyanate 1 (1 mmol) in dry acetone is treated with a 40% aqueous solution of methylamine (3) in dry acetone. This is left to stir at room temperature allowing the in situ generation of aroyl-substituted selenourea 5. After a time, the third component, a solution of phenacyl bromide (2) (1 mmol) in dry acetone, is added to the mixture. This alkylates the selenourea 5 forming intermediate 6, which can undergo cyclization to generate intermediate 7. Tautomerization leading to dehydration occurs generating the final product 4. Six different aroyl groups were subjected to this experiment and produced yields ranging from 76–87%. While this reaction is relatively simple, the proposed mechanism mentioned above is solely based on the assumption that the ‘unsymmetrical selenourea 5 forms from the initial addition of methylamine (3) to aroyl isoselenocyanate 1’ (Scheme 8). This research aims to expand synthetic protocols to effortlessly access organoselenium compounds.

Scheme 8.

Proposed mechanism

3.2.2. Synthesis and X-ray Studies of Diverse Selenourea Derivatives

In 2019 Hua et al. investigated the preparation of a series of N-acylselenoureas and their related heteroatom derivatives through the reaction of KSeCN with an acyl chloride and primary amines, followed by cyclization with phenacyl bromides.⁶⁰ Reacting benzoyl chloride with KSeCN in acetone at room temperature for 3 hours led to the ISC intermediate A. This stable intermediate was treated in situ with 4-bromoaniline at room temperature for another 3 hours to give N-[(4-bromophenyl)carbamoselenoyl]benzamide 8 in 93% isolated yield. This was then subjected to cyclization via the corresponding phenacyl bromide in refluxing acetone to afford organoselenium heterocyclic compounds: N-acyl-1,3-selenazol-2(3H)-imines 9a–c. As expected, these reactions were straightforward and fast, leading to the desired products in high yields (93–96%) (Scheme 9).

Scheme 9.

Synthesis of N-acyl-1,3-selenazol-2(3H)-imines 9a–c⁶⁰

Similarly, 4-methoxybenzoyl chloride was reacted with KSeCN resulting in the in situ formation of stable ISC intermediate B. This was treated in situ with 4-(pentafluorosulfanyl)aniline to provide selenourea 10 in 76% isolated yield. This was then cyclized with 2-bromo-1-(4-methoxyphenyl)ethan-1-one to deliver the expected 1,3-selenazole 11 in a 91% isolated yield (Scheme 10).

Scheme 10.

Synthesis of 1,3-selenazole 11⁶⁰

However, unusual reactivity was discovered when ISC intermediate B was reacted with previously used 4-bromoaniline. Rather than leading to the expected selenourea 12, the unusual non-chalcogen products 2-(4-bromophenylamino)-2-methylpropanenitrile (13) and 6-bromo-1,2-dihydro-2,2,4-trimethylquinoline (14) were isolated in 45% and 52% yields, respectively (Scheme 11).

Scheme 11.

Synthesis of unexpected products 13 and 14⁵⁴

This was an unintentional novel approach accessing these compounds via an ISC intermediate. A mechanism for the formation of products 13 and 14 has not been proposed, however, it seems probable that acetone has a dual role as reagent and solvent.

The reaction between 4-nitrobenzoyl chloride also behaved differently. Treating this substrate with KSeCN and 4-pentafluorosulfanylaniline led to two products: the expected selenourea 15 and the novel side product 3-(4-nitrobenzoyl)imino-5-[4-(pentafluorosulfanyl)phenylamino]-1,2,4-diselenazole (16) in 79% and 19% yields, respectively. Further reactions of selenourea 15 with a range of phenacyl bromides yielded the expected selenium heterocycles 17a–d in high yields (90–93%) (Scheme 12).

Scheme 12.

Synthesis of products 17a–d⁶⁰

Hua’s research⁶⁰ yielded the novel expected and unexpected seleno compounds 8, 9a–c, 10, 11, 15, 16 and 17a–d, along with two unexpected non-chalcogen products 13 and 14. Compound 13 has been previously prepared via catalyzed Strecker reactions using (CH₃)₃SiCN, acetone and amines.^61–63 The preparation of compound 14 has been previously reported via the Skraup reaction of 4-bromoaniline with iodine in refluxing acetone solution,⁶⁴ or via a one-pot reaction using aniline with alkyl vinyl ketone on a silica gel surface saturated with indium(III) chloride under microwave irradiation in neat conditions.⁶⁵ The same group also reported the first novel approach from an ISC intermediate. Only two reported structures are similar to compound 16: 3-benzoylimino-5-(morpholin-4-yl)-1,2,4-diselenazole and 3-dimethylamino-5-phenyl-1,2,4-diselenazolium tetrachloronickelate.⁶⁶ While these two compounds have been synthesized from an ISC starting material, Hua⁶⁰ reported compound 16 as a novel organoseleno-heterocyclic molecule. All of these new seleno compounds were found to be air stable without decomposition over time. Compounds 9a–c, 10, 11, 15, 16 and 17a–d were also subjected to X-ray diffraction studies, revealing intermolecular interactions varying in strength and the type of interaction, e.g., strong NH···N and NH···O hydrogen bonds, weak CH···O, CH···Se and CH···F hydrogen bonds, and weak CH···π and π···π interactions.

3.2.3. Synthesis of Heteroarene-Fused [1,2,4]Thiadiazoles/Selenadiazoles via Iodine-Promoted [3+2] Oxidative Cyclization

Heteroarene compounds, specifically heteroarene scaffolds, are known to be a significant framework in medicinal chemistry and drug discovery due to their presence in several natural and biologically active molecules. Because of this activity, there is a desire to synthesize novel fused heteroarenes containing benzimidazole/oxazole/thiazole cores and 1,2,4-thiadiazoles/selenadiazole rings. Delving into the literature revealed that there are only a few synthetic methods for this. Innovative methods included the synthesis of benzthiazole-fused [1,2,4]thiadiazoles achieved from 2-aminobenzthiazoles and a sulfonyl chloride,⁶⁷ the synthesis of thiadiazolo[3,4-b]benzthiazoles by the reaction of 2-aminobenzthiazoles with 1,1,1-trichloromethanesulfenyl chloride followed by cyclization using aromatic and heteroaromatic amines,⁶⁸ and more recently, benzimidazole-fused 1,2,4-thiadiazoles by using methanesulfonyl chloride in a multistep cyclization involving an intramolecular reaction between carbodiimide and thiourea moieties.⁶⁹ Unfortunately, these methods are limited due to difficulties in accessing the starting materials, low reaction yields, limited substrate scope and harsh reaction conditions using strong acids. In an effort to develop an efficient method, Chen et al. reported novel results on their metal-free synthesis of benzimidazole-fused [1,2,4]thiadiazoles from the reactions of 2-aminobenzimidazole and isothiocyanates (ITC), isoselenocyanates (ISC) and isocyanates.⁷⁰

Chen’s group began with a study of the reaction conditions using 2-aminobenzimidazole (18a) (1.0 equiv) and phenyl isothiocyanate (19a) (2.0 equiv), with different oxidants (0.5–5.0 equiv), bases (3.0 equiv) and solvents over a range of temperatures in order to obtain the desired product, benzo[4,5]imidazo[2,1-c][1,2,4]thiadiazole 20aa (see Table 1). When molecular iodine (0.5 equiv) was introduced as the oxidant, along with K₂CO₃ (3.0 equiv) as the base and chloroform as the solvent at reflux, the desired product 20aa was obtained in a 40% yield (Table 1, entry 1). This reveals the important role of iodine in the formation of 20aa. The number of equivalents of iodine was then doubled (based on 0.5 equiv, giving a 15% increase in yield, Table 1, entry 3) and then increased four-fold (resulting in a 40% increase in yield, Table 1, entry 4). The highest obtained yield of 80% was achieved under the following conditions: 18a (1.0 equiv), 19a (2.0 equiv), I₂ (2.0 equiv), K₂CO₃ (3.0 equiv), chloroform, reflux, 12 hours (Table 1, entry 4). Further solvent and base studies revealed that the mixture mentioned beforehand (Table 1, entry 4) was more appropriate. In addition, the scope of this iodine-promoted reaction was investigated with different 2-aminoheteroarenes 18 and isothiocyanates 19 (see Table S1 in the Supporting Information).

Table 1.

Optimization of reaction conditions to obtain desired product 20aa

Entry	Oxidant (equiv)	Base (equiv)	Solvent	20aa yields (%)
1 b	CH2I2 (5.0)	K2CO3 (3.0)	CHCl3	10
2	I2 (0.5)	K2CO3 (3.0)	CHCl3	40
3	I2 (1.0)	K2CO3 (3.0)	CHCl3	55
4	I2 (2.0)	K2CO3 (3.0)	CHCl 3	80
5	I2 (2.0)	Na2CO3 (3.0)	CHCl3	73
6	I2 (2.0)	Cs2CO3(3.0)	CHCl3	70
7	I2 (2.0)	NaH (3.0)	DMF	0
8	I2 (2.0)	Et3N (3.0)	CHCl3	0
9	I2 (2.0)	DBU (3.0)	CHCl3	15
10	I2 (2.0)	DABCO (3.0)	CHCl3	50
11	I2 (2.0)	K2CO3 (3.0)	ACN	60
12	I2 (2.0)	K2CO3 (3.0)	Toluene	37
13	I2 (2.0)	K2CO3 (3.0)	DMF	48
14	PIDA (0.5)	K2CO3 (3.0)	CHCl3	20
15	NIS (0.5)	K2CO3 (3.0)	CHCl3	0
16	CuI (0.5)	K2CO3 (3.0)	CHCl3	0
17	TBAI (0.5)	K2CO3 (3.0)	CHCl3	0
18 c	I2 (2.0)	K2CO3 (3.0)	CHCl3	0
19 d	I2 (2.0)	K2CO3 (3.0)	CHCl3	80

^aReaction conditions unless otherwise specified: 18a (1.0 equiv), 19a (2.0 equiv), I₂ (2.0 equiv), base (3.0 equiv), and solvent (3.0 mL) at 60 °C for 12 h.

^b20aaa was obtained in 30% yield.

^cAt 25 °C.

^dAt 100 °C.

To further expand the substrate scope, the focus was changed to synthesizing heteroarene-fused [1,2,4]selenadiazoles 22 using isoselenocyanates 21. Aromatic (21a), aliphatic (21b) and cyclic (21c) isoselenocyanates reacted efficiently with 2-aminobenzimidazoles 18 to provide benzimidazo[2,1-c][1,2,4]selenadiazoles 22aa, 22ab, 22ba, 22fa and 22fc in good yields (Scheme 13). 2-Aminobenzoxazole 18′a and 2-aminobenthiazoles 18′c,d were also explored as substrates. Compound 18′a reacted with phenyl ISCs and aliphatic ISCs to give the corresponding products 22′aa and 22′ac in 75% and 64% yields, respectively. 2-Aminobenthiazole 18′c was reacted with the phenyl ISC to afford the desired product 22′ca in a moderate 70% yield (Scheme 13). The reactions with aliphatic (21b) and cyclic (21c) ISCs not only delivered the expected products 22′cc and 22′db in moderate 62% and 68% yields, respectively, but also formed N-alkylated products 23′cc and 23′db.

Scheme 13.

Synthesis of heteroarene-fused [1,2,4]selenadiazoles 22⁷⁰

The proposed formation of N-alkylated products can be explained via a S_N2 pathway: molecular iodine activates isoselenocyanates 21 due to the lone pair of electrons that is available on nitrogen, leading to the formation of intermediate ISC D in which the nitrogen is now positively charged. This allows the amine of 18′c to act as the nucleophile and attacks the ISC substituent while the iodo-ISC becomes the leaving group. The amine is then deprotonated by the remaining negatively charged iodine, leading to the N-alkylated products.

Additionally, these reaction conditions were extended to isocyanate 21d in reactions with 2-aminobenzimidazole 18a and 2-aminobenzthiazole 18′d to give the unexpected urea products methyl 1-(4-methoxybenzyl)-2-(3-phenylureido)-1H-benzo[d]imidazole-5-carboxylate (40% yield) and 1-(6-methoxybenzo[d]thiazol-2-yl)-3-phenylurea (55% yield), instead of the expected products 22ad and 22′dd (Scheme 13).

Investigation into the reaction mechanism was performed by reacting 2-aminobenzthiazole 18′d and phenyl isothiocyanate (19a) in the absence of the iodine oxidant, which gave thiourea 24′da, instead of the expected product 20′da, in a low 15% yield along with unreacted starting material. Product 24′da was then subjected to the standard reaction conditions and underwent intermolecular C–S bond formation followed by desulfurization to afford new product 25′da in 55% yield. To see if a radical pathway was possible, 2-aminobenzimidazole 18a and phenyl isothiocyanate (19a) were reacted along with TEMPO (as a radical scavenger) under the optimized reaction conditions, yielding the previously obtained desired product 20aa in 70% yield (Scheme 14).

Scheme 14.

Mechanistic studies⁷⁰

This result suggests that this reaction does not go through a radical pathway. Thus, a mechanism was proposed with isothiocyanates but can also be further applied with isoselenocyanates. The electron rich C=S bond of the isothiocyanate reacts with molecular iodine to generate an activated species I. The highly nucleophilic endo-nitrogen (N³) of the 2-aminoheteroarene will attack the electrophilic carbon of the activated iodo-isothiocyanate I to form a C–N bond. This is followed by oxidative iodination to give iodo-intermediate II followed by deprotonation to give iodo-intermediate III. This intermediate can undergo S–N bond formation in an S_N2-like mechanism via intramolecular nucleophilic attack of the exo-nitrogen (N¹) to generate intermediate IV. Lastly, base-mediated deprotonation generates the desired product 20 (Scheme 15).

Scheme 15.

Proposed mechanism⁷⁰

Chen et al. have reported a metal-free and highly versatile synthetic approach towards accessing two novel classes of heteroarene-fused [1,2,4]thiadiazoles and [1,2,4]selenadiazoles via an iodine-mediated [3+2] oxidative cyclization of 2-aminoheteroarenes using both isothiocyanates and isoselenocyanates.⁷⁰ The desire for these types of heteroarenes is high as the potential for biological activity can offer a range of therapeutics. This clever protocol utilizes a series of 2-aminobenzimidazole derivatives that are essentially coupled to highly versatile intermediates, such as phenyl, aliphatic and cyclic isoselenocyanates.

3.2.4. 2-Amino-1,3-selenazole Derivatives via Base-Promoted Multicomponent Reactions

Because selenazoles have been reported to have good biological activity, interest in using these derivatives is high. Although multiple synthetic strategies have been used towards accessing these molecules, a common method employs the Hantzsch condensation to construct 1,3-selenazoles. In an effort to expand the synthetic protocols, Liu et al. reported a novel synthesis of 2-amino-1,3-selenazoles using a multicomponent reaction of α,β-unsaturated isocyanides, elemental selenium, and amines for the synthesis of 2-amino-1,3-selenazoles in moderate to excellent yields. The reaction involves the in situ formation of isoselenocyanates (ISCs) from isocyanides and elemental selenium powder, intramolecular cycloaddition, and aromatization.⁷¹

Optimization was achieved with ethyl 2-isocyano-3-phenyl-acrylate (26a) (0.10 mmol), elemental selenium (27) (0.15 mmol) and diethylamine (28a) (0.15 mmol) in the presence of a base (0.15 mmol) and solvent (1 mL) at 30 °C (see Table S2 in the Supporting Information). The optimum conditions were met when DBU and DMSO were used as the base and solvent, respectively, with the reaction being complete after 18 hours to afford the desired product, ethyl 2-(diethylamino)-5-phenyl-1,3-selenazole-4-carboxylate (29a) in 69% yield, along with a trace amount of the undesired byproduct, ethyl 2-(diethylamino)-4,5-dihydro5-phenyl-1,3-selenazole-4 carboxylate (30a) (Figure 3).

Figure 3.

Structures of products 29a and 30a⁷¹

Using the optimum conditions, an investigation of the isocyanide substrates was performed (Scheme 16). Because the preparation of these isocyanides produces mixtures of E and Z configurations, both isomers were investigated to determine the reactivity. When ethyl (Z)-2-isocyano-3-(4-methoxyphenyl)acrylate (26e) was used, product 29e was obtained in 76% yield. When the E configuration was used, the yield decreased significantly to 42%. Because of this, only Z isocyanide configurations were used for further studies. Isocyanides bearing weakly activating electron-donating groups (EDG) at ortho, meta and para positions of the aromatic ring participated in the reaction to afford the desired products 29b–e in good yields (67–76%). Isocyanide 26b underwent both a small-scale and large-scale reaction with similar yields being observed. When no substituents were present on the aromatic ring, the reaction produced product 29f in a moderate 56% yield. When a strongly activating EDG was present (26g), the reaction produced 29g in a moderate 45% yield. To investigate alkene reactivity, electron-withdrawing groups (EWG), such as CONR¹R², were substituted at the double bond, however, the reaction failed completely. In contrast, strongly electron-withdrawing groups (EWG) on the aromatic ring did allow the reaction to proceed. Both CF₃ and CN groups (26h and 26i, respectively) gave the corresponding products 29h and 29i in low yields. The aromatic CN group most likely reacted with elemental selenium. Using a weaker EWG, fluorine, on the para position produced product 29j in a good 68% yield. Finally, the six membered aromatic ring was replaced with the aromatic heterocycles thiophene (26k) and furan (26l), but only the isocyanide containing a 2-thienyl group generated the desired product 29k in a moderate 57% yield.

Scheme 16.

Investigations on isocyanide substrates⁷¹

Next, the scope of the amine substrates was explored (Scheme 17). Aliphatic secondary amines 28m,n yielded products 29m,n in 76% and 78% yields. N-Methylethanolamine 28o also underwent a successful reaction to give product 29o in 80% yield. Replacing the hydroxy group with a cyano EWG decreased the yield to 25%. Cyclic amines such as pyrrolidine 28q, piperidine 28r, morpholine 28s and 5,6,7,8-tetrahydroisoquinoline 28t gave the resulting products 29q, 29r, 29s and 29t in yields of 42%, 48%, 35% and 50%, respectively; these low to moderate yields revealed acyclic secondary amines to be more reactive. The secondary amine fluoxetine (antidepressant) was also used and produced target product 29u in a moderate 53% yield.

Scheme 17.

Amine substrate investigation⁷¹

Mechanistic studies were begun by observing the transformation of 30a into the desired product 29a in the presence of DMSO and DBU on heating at 30 °C for 12 hours (Scheme 18). Product 29a was observed in 69% yield, suggesting that oxidation of 30a is a crucial step. To see if the in situ generation of isoselenocyanates was possible, compound 26b and elemental selenium (27) were reacted together using the same solvent and temperature to yield isoselenocyanate 31a in an excellent 93% yield. This was confirmation that elemental selenium readily selenates the isocyanide functional group. ISC 31a was then subjected to amination with diethylamine (28a) in DMSO at 30 °C and after one hour, the in situ formation of 32a was observed. This was taken a step further by introducing DBU under the standard conditions, which afforded previously synthesized product 29b in a 73% yield. Being able to control the reaction by isolating the intermediates has revealed that the formation of ISC 31a and amination product 32a are crucial steps in the mechanism. In order to determine if DMSO is also working as an oxidant, the synthesis of product 29b was performed again under the standard conditions while under an argon atmosphere. Product 29b was again obtained in 73% yield. Liu’s research group performed HRMS analysis of the residue and detected the molecular weight of dimethyl sulfide, which indicated DMSO did act as an oxidant. Because they found that during optimization MeCN produced 29a in 46% yield, it is possible that oxygen is also involved in the reaction as an oxidant. In a similar way, the synthesis of 29b was set up, however, this time using MeCN under argon. Only a trace amount of product 29b was found, which confirms that both DMSO and oxygen work as oxidants in this reaction (Scheme 18).

Scheme 18.

Mechanistic studies⁷¹

Taking into account the mechanistic studies, the following mechanism is proposed. Isocyanide 26 is readily selenated by elemental selenium forming in situ ISC E. The electrophilic carbon of the ISC group is targeted by nucleophilic amine 28 and forms intermediate F. The amine is subjected to deprotonation by DBU to form selenium anion intermediate G. This is followed by an intramolecular Michael addition and protonation to form 30. Finally, 30 is oxidized by DMSO and oxygen to furnish the final product 29 (Scheme 19).

Scheme 19.

Proposed mechanism⁷¹

Liu et al. have provided a moderate to high yielding practical synthetic pathway to synthesize a range of 2-amino-1,3-selenazoles via a base-promoted cascade cyclization. While more traditional methods use harsh procedures, the method provided by Liu uses mild conditions and proceeds via the multicomponent reactions of α,β-unsaturated isocyanides and elemental selenium, to generate in situ ISCs, with nucleophilic amines, without the need of transition metals as catalysts or protection protocols involving an inert atmosphere.

4. Conclusion

Without question, selenium has an important role in human health. Since the first studies of this element, knowledge of what selenium compounds can do has expanded. Of major interest is the ability of organoselenium compounds to hinder the initiation and post-initiation phases of chemical carcinogenesis, while also exhibiting antitumorigenic, anti-angiogenic and pro-oxidant activity in cancer cells. Organoselenium compounds are proposed to induce DNA damage, regulate the cell cycle, inhibit cellular growth, induce apoptosis and generate reactive oxygen species. This biological activity sparks interest in the field of selenium chemistry to access and evolve therapeutics in the fight against cancer and other diseases.

Isoselenocyanates (ISCs) are key selenium intermediates. The studies shown here all utilize ISCs to afford a range of novel organoselenium heterocycles. Although much of the reviewed work did not mention biological studies, it is important to establish good synthetic protocols in order to advance the field of selenium chemistry. Some of these protocols ‘fine-tune’ already established named reactions and others simply use the reactivity of ISCs to generate different scaffolds. These studies give insight towards both expected and unexpected reactivity trends of ISCs and the stability of ISCs for use as starting materials or generated in situ. ISCs have major potential to help shape multiple fields in chemistry. As research has shown, they are particularly promising in the field of medicinal chemistry due to their biological activity in the context of cancer and human diseases. As synthetic methods towards accessing ISCs evolve, their importance will drastically increase. ISCs have already proven to be effective intermediates for the synthesis of selenocarbamates, heterocycles, and selenoureas, all of which are biologically active. With more research and structural optimization, it is anticipated that ISCs and organoselenium compounds derived from ISCs will evolve to work as potential pharmaceutical agents or as additional key intermediates towards accessing a range of novel organoselenium compounds.

Supplementary Material

Supporting Information

Supporting information for this article is available online at https://doi.org/10.1055/a-1370-2046.

Biographies

Raul Neri (left) received two bachelor of science degrees in biomedical chemistry and general chemistry from Kansas Wesleyan University in 2018. He is currently working towards a Ph.D. in organic chemistry at Kansas State University under the guidance of Dr. Stefan H. Bossmann

Stefan H. Bossmann (right) received his Ph.D. in chemistry in 1991 from the University of Saarland, Germany (Ph.D. adviser: Prof. Dr. Heinz Dürr). He was a postdoctoral fellow at Columbia University in the City of New York with Prof. Dr. Nicholas J. Turro from 1991–1993. He obtained his Habilitation in Chemical and Process Engineering in 1998 from the University of Karlsruhe, where he was named ‘Außerordentlicher Professor’. From 2004 to 2020, he was a full professor of chemistry at Kansas State University, USA and received the honor of University Distinguished Professor in 2019. In 2020 he became professor of cancer biology at The University of Kansas Medical Center, USA.