Regioselective one-pot three component synthesis of chiral 2-iminoselenazolines under sonication

Abstract

A one-pot multi component reaction of selenoureas, which are in situ generated from L-amino esters and isoselenocyanates, with α-bromoketone under ultrasonication. Selenourea and α-bromoketones formed 2-iminoselenazoles through a Hantzsch selenazole-type reaction. The steric effect of the α-substituted bromoketones on the rate of the tandem reaction was studied to understand the reaction mechanism by isolating the key reaction intermediate, 2-iminoselenol.

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Introduction

Functionalized organoselenium compounds serve as useful synthetic reagents and exhibit a wide range of biological properties such as antitumor, antimicrobial and antioxidant activities.¹ The synthesis of isosteric selenium analogs of biologically active sulphur compounds has often resulted in molecules with a higher potency than their parent counterparts.^1d,2 For example, imidazoline-2-selone as an inhibitor of thyroid peroxidase (TPO) displayed a higher antioxidant activity than that of thione analogs.³ There are few representatives of bioactive organoselenium compounds, such as imidazoline-2-selone and selenouracil, which are potent inhibitors of the LPO-catalyzed oxidation of anti-thyroid drugs.^4,5 Selenazofurin is a blocker of IMP dehydrogenase, and 2-acylamido selenazoles display anti-SOC channel activity (Fig. 1).^6,7 Other structures such as selenocysteine are employed in the synthesis of artificial proteins to probe the function of target selenoproteins in the human body.⁸ This motivated us to study the synthesis of structurally related 2-iminoselenazolines which may provide new pharmaceutical profiles. Some publications report the use of thiourea and α-bromoketones to synthesize 2-iminthiazoles.⁹ In addition, the synthesis of 2-iminoselenazoles has rarely been studied, and only a few methods for the synthesis of selenium–nitrogen heterocycles have been reported.¹⁰ The reactions of N-containing nucleophiles such as β-haloamines and propargyl amines with aryl or alkyl isoselenocyanates have been utilized for the synthesis of 1,3-selenazolidin-2-imines.¹¹ Another reported synthesis of pure chiral selenazolidines was the reaction of chiral isoselenocyanates in aqueous ammonia.¹² The reaction of readily available enantiopure α-aminoacids/esters is relatively unexplored for such transformations. Therefore, developing an efficient method to synthesize 2-iminoselenazoline is of great interest to academia and the pharmaceutical industry. Herein, we studied the incorporation of selenium atoms into the heterocyclic rings of aryl or alkyl isoselenocyanates in the synthesis of 2-iminoselenazolines through multicomponent coupling reactions.

Fig. 1 Structurally related biologically active organoselenium compounds.

Multicomponent reactions (MCRs) are a powerful synthetic tool for the rapid and efficient construction of complicated molecular frameworks. Their flexibility to generate structural diversity and their incorporation of molecular complexity in a one-pot operation is well-recognized.¹³ The essential rule of avoiding the isolation and purification of the intermediates in one-pot reactions is a major factor to speed up the synthesis of drug-like compounds.¹⁴ MCRs are strategically amenable with modern synthetic tools such as microwave irradiation, ultrasonication, and polymer and ionic liquid-supported synthesis. The combination of these techniques is a driving force to discover new MCRs. Ultrasonication employs a non-electromagnetic radiation source of sound energy to induce chemical reactions through acoustic cavitations. Ultrasonication also accelerates chemical reactions by improving the mixing of reactants and the mass and heat transfers in the reaction medium.¹⁵ The ultrasound accelerated three component coupling syntheses of tetrahydropyrimidines,¹⁶ phthalazinones,¹⁷ spirooxindoles¹⁸ and azoles¹⁹ have demonstrated their efficiency in multicomponent reactions.

In view of the power associated with ultrasonication and the biological importance of selenium analogs, we report a three component coupling reaction toward selenium-containing heterocycles. These telescoped reactions of L-amino esters, isoselenocyanates and α-substituted bromoketones for the regioselective synthesis of enantiopure 2-iminoselenazolenes under ultrasonication were explored in a one-pot manner.

Results and discussion

Initially, we tested the reactivity of L-aminoesters 2 with various aryl- and alkyl-isoselenocyanates 1, for the synthesis of selenium containing heterocycles from selenourea.²⁰ The required isoselenocyanates were synthesized using modified literature procedures from N-formylamines with various amines (R₁NH₂) under sonication. Accordingly, N-formamide, triphosgene and triethylamine in dichloromethane were refluxed to generate an isocyanide intermediate, which was further reacted with selenium powder to produce isoselenocyanates in a one-pot manner (Scheme 1). The isolated yields were much higher than those previously reported on the application of sonication.²¹ The structure of compound 1f was confirmed using X-ray analysis (Fig. 2).

Scheme 1 One-pot synthesis of isoselenocyanate 1.

Fig. 2 X-ray crystal structure of 1f.

With the successful preparation of isoselenocyanates, we began to react L-phenylalanine methyl ester 2d with phenyl selenoisocyanate 1d to deliver the intermediate selenourea 3d within 30 min. The addition of phenacyl bromide to the above-mentioned reaction mixture led to the formation of 2-seleniimidazole 5d in 52% yield. Based on this observation, we attempted to develop a one-pot procedure without prior isolation of selenourea 3. The 2-seleniimidazole 5d was obtained in 72% yield following the one-pot protocol, which is higher than that of the stepwise reaction (52%). To explore the reaction conditions, a series of experiments using L-amino acid methyl esters, isoselenocyanates, and α-bromoketones with varying reaction parameters were performed (see ESI†). In order to accelerate the coupling reactions, we also applied microwave irradiation in various solvents such as THF, acetonitrile, MeOH, DMF, and H₂O for the same reaction stoichiometry. When an external base was added to the reaction mixture, intermolecular cyclization was performed first to deliver selenohydantoin, which was not our desired selenourea 3.

Although microwave irradiation increased the reaction yield and diminished the reaction time in some cases,²² this harsh condition could cause decomposition and racemization of temperature sensitive compounds such as chiral amino acids, carbonyl compounds, etc.²³ Moreover, selenourea is a well-known air and light sensitive molecule; it is necessary to develop a mild reaction process such as sonication to synthesize 2-iminoselenazolines.²⁴ We used ultrasonication to accelerate the reaction progress in various solvents such as THF, acetonitrile, MeOH, DMF, and H₂O. The compound 5a was finally obtained in 80% yield under sonication in acetonitrile.²⁵

To ensure that the stereochemistry of 5d remains unaffected during these transformations, the other enantiomer 5d′ was synthesized from D-phenylalanine methyl ester. The chiral HPLC analysis of the products 5d and 5d′ confirmed the complete conservation of the enantiomeric purity (see ESI†). As shown in Table 1, we summarized this reaction with miscellaneous reagents and starting materials. Treatment of α-aminoesters 2 with isoselenocyanates 1 under ultrasonication at room temperature delivered the corresponding selenourea 3 within 5 min in acetonitrile. The same reaction required a 30 min reflux to reach completion. Further treatment of the crude reaction mixture with various bromoketones (4a–l) led to the formation of 2-iminoselenazoles (5a–l) after 30 min sonication (Table 1). This observation also contributes to the study of the ultrasonic effect and the effect of thermal refluxing conditions on the rates of the reactions. For example, with the same stoichiometry, it took 3 hours to synthesize 5a under reflux in CH₃CN. The structure of compound 5f was further confirmed using X-ray analysis (Fig. 3).

Table 1 One-pot two-step synthesis of 2-iminoselenazoles from α-bromoketones, isoselenocyanates, and L-aminoesters

Entry	R^1	R^2–N=C=Se		Yield^d
a Reaction conditions: L-aminoesters (2, 1.0 mmol), isoselenocyanates (1, 1.5 mmol), α-bromoketones (4, 1.5 mmol), MeCN (10 ml), rt, step two 30 min, total 35 min.b Reaction conditions: L-aminoesters (2, 1.0 mmol), isoselenocyanates (1, 1.5 mmol), α-bromoketones (6, 1.5 mmol), MeCN (10 ml), rt, step two 90 min, total 95 min.c Reaction conditions: L-aminoesters (2, 1.0 mmol), isoselenocyanates (1, 1.5 mmol), α-bromoketones (8, 1.5 mmol), MeCN (10 ml), rt, step two 60 min, total 65 min.d Isolation yields.
5a				80%
5b				77%
5c				67%
5d				59%
5e				80%
5f				73%
5g				79%
5h				84%
5i				90%
5j				75%
5k				67%
5l				78%
7a				66%
7b				85%
7c				83%
7d				80%
7e				78%
7f				78%
9a				82%
9b				42%
9c				67%

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Fig. 3 X-ray crystal structure of 5f.

The formation of selenazoles is favorable through Se-alkylation over N-alkylation followed by regioselective cyclization to generate product 5, according to a recent report regarding the reaction of N,N′-biaryl selenourea with phenacyl bromide.^9a Such a condensation of selenourea, with enolizable ketones and bromine is well-known as the Hantzsch synthesis.²⁶ However, the interplay of the ambident N vs. Se nucleophilicity leading to the ambiguous structural interpretation of imidazol-2-selenone or selenone-2-imine prompted us to study the reaction mechanism in more detail.²⁷ We performed the condensation of selenoureas with α-bromoketones to synthesize 2-iminoselenazolines within 90 min (Table 1, 7a–f). The structure of compound 7a was confirmed using X-ray analysis (see ESI†). Secondary α-bromoketones are rarely used for Hantzsch selenazole-type condensations due to their low reactivity. The α-substituted bromoketones required a higher sonication time compared to that used for the unsubstituted bromoketones, due to steric hindrance. We utilized this fact to study the reaction mechanism with the possible isolation of reaction intermediates. The treatment of selenourea 3 with α-phenyl phenacyl bromide 8 under ultrasonication in acetonitrile for 40 min confirmed complete conversion into a new product, which was characterized to reveal the formation of 4,5-diphenyl 2-imino 4-hydroxy 1,3-selenazolidin 10 as a possible reaction intermediate (Scheme 2). The structural characterization of 10 was also confirmed using X-ray crystallographic analysis (Fig. 4). Similar results and observations have also been reported by Egan and Tadanier on the Hantzsch thiazole synthesis.^26a We synthesized a series of compounds, 9a, 9b, and 9c, to test the reactivity difference of the R₁ and R₂ groups with 2-bromo-1,2-diphenylethanone. The dehydrated 2-iminoselenazole 9 (Table 1, 9a–c) was eventually obtained under prolonged sonication for 60 min. Compound 9a was less sterically bulky to obtain higher yields, but compound 9b with sterically bulky groups R₃ and R₁ leads to less yield. Current studies have been restricted to benzoin condensation, ester hydrolysis, and dichlorocyclopropanation and there is a paucity of data to rationalize the steric effects in terms of the bulkiness of the two carbon electrophiles in such cyclization reactions.^28–30 Summarization of the reaction times of selenourea with three kinds of α-bromoketone shows that the reaction using the primary α-bromoketone was rapid (35 min), the one using 2-bromo-1,2-diphenylethanone was milder (65 min), and the one with 2-bromopropiophenone was slower (95 min).

Scheme 2 One-pot synthesis of 4,5-diphenyl 2-imino-4-hydroxy 1,3-selenazolidin 10.

Fig. 4 Structure of the 4-hydroxy-4,5-diphenyl-2-(phenylimino)-1,3-selenazolidin-3-yl)-3-phenylpropanoate 10.

Thus in the presence of anhydrous acetonitrile, selenourea reacts via the soft nucleophile Se with the soft electrophilic C–Br bond (Fig. 5). The subsequent transformation involves the loss of a proton from N₁ and the intramolecular nucleophilic attack of N₂ (hard nucleophile) on the carbonyl group of the ketone (hard electrophile) to deliver 2-iminoselenol 10 which, upon subsequent dehydration, releases the observed 2-iminothiozole 5, 7, and 9 products (Scheme 3). From our supposition, N₂ was more reactive than N₁ because N₁ was near the electron-withdrawing carbonyl group of the amino ester, causing regioselectivity. Therefore, the formation of the 2-iminoselenazoles 5, 7, and 9 is due to the preferential attack of selenium because of its enhanced nucleophilicity, and the driving force for the selective N₁ attack on the alkyl carbon is to eliminate a stable hydrobromide salt. Furthermore, the influence of steric factors on the reaction time has been effective to characterize the intermediate 2-imino-5-selenol 10, which undoubtedly confirmed that selenourea reacts via a soft nucleophile group (i.e. the selenium atom).

Fig. 5 Various reactive sites in selenoureas and α-bromoketones.

Scheme 3 A plausible mechanism for the formation of 2-iminoselenazoles 5, 7, and 9.

In conclusion, we explored a regioselective synthesis of polysubstituted 2-iminoselenazoles through the reaction of in situ generated selenoureas with α-bromoketones under environmentally benign ultrasonic activation at room temperature. We understand that the reaction mechanism passes through an N₁ selenourea intermediate after the reaction of the soft nucleophile Se with the soft electrophilic C–Br bond to form the 2-iminoselenazole. The intermediate of a dihydro selenol in the construction of 2-iminoselenazolines has been conclusively established in the seleno Hantzsch reaction. An efficient synthesis of enantiopure 2-iminoselenazoles from readily available building blocks may help to discover novel biological profiles for these diverse skeletal scaffolds.

Acknowledgements

The authors thank the Ministry of Science and Technology (MOST, Taiwan) for financial assistance. Many thanks for the help from the X-ray crystallographic operators, Pei-Lin Chen (NTHU) and Ting-Shen Kuo (NTNU), to obtain 1f, 5f, 7a and 10. This work is particularly supported by the “Center for Bioinformatics Research of Aiming for the Top University Program” of the National Chiao Tung University and Ministry of Education, Taiwan.

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Footnote

† Electronic supplementary information (ESI) available: Spectroscopic data of essential intermediates and final compounds as well as X-ray data of compounds 1f, 5f, 7a, and 10. CCDC 1424392, 883326, 885567 and 883327. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra18763j

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