30.5.6 Selenium- and Tellurium-Containing Acetals (Update 2016)

M. Yoshimatsu

General Introduction

In the last decade, much attention has been paid to selenium- and tellurium-containing acetals with a view to producing therapeutically useful agents with antiviral^[1,2] and antitumor^[3] activities. The development of clinical and biochemical probes using first-generation nucleosides (i.e., 4′-oxonucleosides)^[4,5] and second-generation nucleosides (i.e., 4′thionucleosides and carbonucleosides)^[6–12] has stimulated research into new selenonucleosides (i.e., third-generation nucleosides) that contain Se, N-acetal structures. A convenient method for producing 4-selenosugars starting from D-ribose was developed in 2008, and a wide range of synthetic procedures using seleno-Pummerer condensation with nucleobases has been investigated.^[13] Despite the lability of the selenoxides, some procedures such as oxidation at a low temperature (i.e., –78 °C) and treatments using flash chromatography have made the key step in the seleno-Pummerer reactions possible. The first syntheses of 4′-selenonucleosides with pyrimidine bases (i.e., uridine, cytosine, and thymidine) were successfully reported.^[13] In contrast, the selenoglycosides of purines (adenine and guanine) are not common, and only a few nonregioselective procedures have been reported. More comprehensive and improved methods that may be used to produce new DNA or RNA building blocks have been reported.^[14,15] Some Se, N-acetals can form complexes with transition metals, and some of these complexes can catalyze useful coupling reactions, such as Suzuki coupling.^[16] Recently published methods could open up new applications in this field. This chapter is an update to Section 30.5, describing recent advances in the synthesis and applications of selenium- and tellurium-containing acetals.

30.5.6.1 S, Se-and S, Te-Acetals

30.5.6.1.1 Method 1: Reaction between Selenium Dihalides and Divinyl Sulfide or Divinyl Sulfone

Divinyl sulfides and sulfones 1 react with selenium dichloride or dibromide to give, via a seleniranium ion, two kinds of cyclic S, Se-acetal [2,4-bis(halomethyl)-1,3-thiaselenetanes 2 (X = S) and 5-halo-2-(halomethyl)-1,3-thiaselenolanes 3 (X = S)], and their corresponding 1,1-dioxides (▶ Scheme 1).^[17,18] The reaction of 2-(bromomethyl)-1,3-thiaselenole (i.e., 4, X = S; Z = Br) with ethanolic potassium hydroxide leads to 2-ethoxy-2,3-dihydro-1,4-thiaselenine 5 (Nu = OEt) in good yield,^[17–19] and reacting 4 (X = S; Z = Br) with sodium acetate has been found to give 2-acetoxy-2,3-dihydro-1,4-thiaselenine (5, Nu = OAc).^[19,20] However, carbon nucleophiles were found to attack the selenium atom on the intermediate 4 (X = S; Z = Br) to cause ring opening, e.g. to form (Z)-3-{[2-(vinylsulfanyl)vinyl]selanyl}butan-2-one (6).^[20]

Scheme 1 Reaction between Selenium Dihalides and Divinyl Sulfides or Sulfones^[17–20]

30.5.6.1.2 Method 2: Selanylation–Deselanylation Process To Introduce a C=C Bond

S, Se-Acetals have been used as synthetic intermediates in the synthesis of (+)-fusicoauritone derivatives, to introduce a C=C bond during the construction of a dolabelladiene.^[21] Thus, the phenylselanylation of α-keto sulfone 7 proceeds upon treatment with sodium hexamethyldisilazanide followed by benzeneselenenyl chloride (▶ Scheme 2). β-Elimination of the selanyl group using hydrogen peroxide affords the novel Nazarov cyclization precursor 8.

Scheme 2 Selanylation–Deselanylation of an α-Keto Sulfone^[21]

The (α-organoselanyl)methyl sulfone 9 has also been lithiated, alkylated with aldehydes to afford intermediates 10, and then deselanylated to afford the corresponding Morita–Baylis–Hillman adducts 11 (▶ Scheme 3).^[22,23] These products have been used in intramolecular cyclization reactions to give [m.n.0]-bicyclic compounds with a nitrogen at the bridgehead position.

Scheme 3 Alkylation and Deselanylation of Lithiated (Organoselanyl)methyl Sulfones^[22]

30.5.6.1.3 Method 3: Electrochemical Fluoroselanylation of Vinyl Sulfones

The electrochemical fluoroselanylation of vinyl sulfones proceeds in the presence of diphenyl diselenide and triethylamine–hydrogen fluoride in nitromethane (▶ Scheme 4).^[24] However, the yield is lower for the desired product than in related reactions of α,β-unsaturated carbonyl compounds.

Scheme 4 Electrochemical Fluoroselanylation of Vinyl Sulfones^[24]

30.5.6.2 Se, Se-and Se, Te-Acetals

30.5.6.2.1 Method 1: Palladium-Catalyzed Double Hydroselanylation of Alkynes

Palladium(II) acetate catalyzes the addition of organoselenols to alkynes via Markovnikov addition, with alkenyl selenides formed exclusively.^[25,26] However, the formation of insoluble metal selenide aggregates results in these metal-catalyzed addition reactions not going to completion. The formation of these aggregates can be suppressed by using a large excess of the alkyne and by adding acetic acid to coordinate the metal selenides. This has enabled the double hydroselanylation of alkynes to be achieved, producing 2,2-bis(phenylselanyl)alkanes 12 (▶ Scheme 5).^[25,26] To identify the mechanism involved, the hydroselanylation of the vinylic selenides 13 that are formed under the above-mentioned conditions was examined. Protonolysis with acetic acid was found to play an important role in the formation of the Se, Se-acetals; the acetic acid inhibits the aggregation of the active palladium diorganoselenide species.

Scheme 5 Palladium-Catalyzed Double Hydroselanylation of Terminal Alkynes^[25,26]

Reactions between methylenecyclopropanes 14 and diphenyl diselenide in dichloromethane catalyzed by titanium(IV) chloride afford 1,1-bis(organoselanyl)cyclobutanes 16 in moderate to good yields (▶ Scheme 6).^[27] It is well known that diorganyl diselenides react with Lewis acids to give highly reactive cationic species;^[28,29] the active species first reacts with the methylenecyclopropane to form an episelenonium ion intermediate, which undergoes C—Se bond fission and rearrangement to give the more stable α-organoseleno carbocation 15. Nucleophilic attack of the organoselenolate anion affords the Se, Se-acetal. The relief of ring strain in the methylenecyclopropane drives this reaction.

Scheme 6 Lewis Acid Catalyzed Selanylation of Methylenecyclopropanes^[27]

1,1-Bis(phenylselanyl)cyclobutanes 16; General Procedure:^[27]

In a Schlenk tube, the methylenecyclopropane 14 (0.22 mmol) and (PhSe)₂ (0.2 mmol) were dissolved in CH₂Cl₂ (0.5 mL) under a N₂ atmosphere. The mixture was kept at –75 °C and a 0.2 M soln TiCl₄ (0.5 mL) was added at this temperature. The mixture turned red immediately and was stirred overnight. The temperature rose gently to rt, and then H₂O (5 mL) was added and the mixture was extracted with CH₂Cl₂ (3 × 5 mL). The combined organic layer was dried (Na₂SO₄). The solvent was evaporated under reduced pressure and the residue was isolated by preparative TLC (petroleum ether/EtOAc 10:1).

30.5.6.2.3 Method 3: Indium/Chlorotrimethylsilane Promoted Selenoacetalization of Aldehydes Using Diorganyl Diselenides

Indium/chlorotrimethylsilane promotes the selenoacetalization of aliphatic aldehydes using commercially available diphenyl diselenide, with good yields of the products obtained (▶ Scheme 7). Unfortunately, reactions with aromatic aldehydes do not produce the expected selenoacetals 17, but instead lead to monoselenides 18 because of radical cleavage of the C—Se bond in the acetal that initially forms. In contrast, indium/chlorotrimethylsilane promotes thioacetalization to afford the corresponding S, S-acetal in reactions with both aromatic and aliphatic aldehydes.^[30,31]

Scheme 7 Indium/Chlorotrimethylsilane Promoted Selenoacetalization of Aldehydes^[30,31]

30.5.6.2.4 Method 4: Diselanylation of Dihaloalkanes with 1-(Organoselanyl)perfluoroalkanols

Organoselenols have been used as starting materials in the syntheses of various selenium compounds. However, organoselenols are labile under air and are easily oxidized to give diorganyl diselenides. Nevertheless, relatively stable reagents exist that provide synthetic equivalents of organoselenols, including trimethyl(phenylselanyl)silane,^[32,33] tris(phenylselanyl)borane,^[34] and diisobutylaluminum benzeneselenolate^[35–37] (see Section 30.5.2.1.2.2). 1-(Organoseleno)perfluoroalkanols 19 have been used as reagents to release organoselenols, which react with dihalomethanes to give bis(organoselanyl)methanes, e.g. 20, in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (▶ Scheme 8).^[38]

Scheme 8 Selanylation Using a 1-(Organoselanyl)perfluoroalkanol^[38]

2,2,3,3,4,4,4-Heptafluoro-1-(phenylselanyl)butan-1-ol (19):^[38]

A 1 M soln of iBu₂AlH in toluene (25.0 mL, 25 mmol) was added to (PhSe)₂ (3.20 g, 10.3 mmol) at 0 °C under an argon atmosphere. The mixture was cooled and 1-ethoxy-2,2,3,3,4,4,4-heptafluorobutan-1-ol (ca. 60%; 20.7 mmol) was added. The mixture was stirred for 1.5 h at rt, and then 1 M HCl in EtOH (2.0 mL) was added dropwise to the mixture at 0 °C. The mixture was poured into 1 M HCl (200 mL) and the organic and aqueous layers were separated. The aqueous layer was extracted with Et₂O (2 × 20 mL). The organic layers were combined and dried (MgSO₄), and the solvent was removed under reduced pressure. The title compound was obtained as an orange oil, and could be used without further purification; yield: 4.87 g (66%).

Bis(phenylselanyl)methane (20); Typical Procedure:^[38]

To a THF (3.0 mL) soln of selenide 19 (0.71 g, 2.00 mmol) and CH₂I₂ (0.27 g, 1.00 mmol) was added DBU (0.15 g, 1.00 mmol) at 0 °C. The mixture was stirred for 30 min and then poured into H₂O (50.0 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layer was dried (MgSO₄) and the residue was purified by preparative TLC (silica gel, hexane) to afford a yellow oil; yield: 0.23 g (70%).

30.5.6.2.5 Method 5: Diselanylation of Dihaloalkanes Using Selenolate Anions

A 16-membered diselenatriaza macrocycle, 6,7,8,9,10,11,12,13-octahydro-5H-dibenzo[d, o][1,3]diselena[7,10,13]triazacyclohexadecine (21), has been prepared through the reaction between sodium selenolate anions (generated in situ) and dibromomethane, reaction of the resulting Se, Se-acetal with diethylenetriamine, and reduction of the resulting diimine using sodium borohydride (▶ Scheme 9).^[39] A pinkish white precipitate, with a 1:1 composition, was found when the product was used in a complexation study with silver(I) perchlorate. The⁷⁷Se NMR spectrum of the complex exhibits a peak at δ 424, which is downfield shifted by about 120 ppm compared to the peak for the free compound (at δ 303).

Scheme 9 Synthesis of an Se, Se-Acetal-Containing Macrocycle^[39]

30.5.6.3 Te, Te-Acetals

30.5.6.3.1 Method 1: In Situ Generation and Reaction of Tellurocarbamates with Dihaloalkanes

The generation and reaction of tellurocarbamates with dihaloalkanes affords Te, Te-acetals in yields of 8–68% (▶ Scheme 10).^[40,41]

Scheme 10 In Situ Generation and Reaction of Tellurocarbamates with Dihaloalkanes^[40,41]

30.5.6.4 Se, N-Acetals

30.5.6.4.1 Method 1: Phosphoric Acid Catalyzed Addition of Benzeneselenol to an N-Acylimine

The addition of benzeneselenol to an aromatic N-benzoylimine, catalyzed by a chiral (R)BINOL-based phosphoric acid, gives Se, N-acetal 22 in excellent yield and with excellent enantioselectivity (▶ Scheme 11; single example reported).^[42]

Scheme 11 Phosphoric Acid Catalyzed Addition of Benzeneselenol to an N-Benzoylimine^[42]

(R)-N-[Phenyl(phenylselanyl)methyl]benzamide (22):^[42]

To a flame-dried reaction tube equipped with a septum and a stirrer bar was added the N-acylimine (0.1 mmol) and the R-phosphoric acid catalyst (2 mol%). The tube was evacuated and then filled with argon. Dry toluene (1.0 mL) was added to the mixture, followed by PhSeH (0.12 mmol) via syringe. The reaction was stirred at rt for 5 min. The crude product was purified directly by flash column chromatography (hexane/EtOAc 2:1) to give the Se, N-acetal product; yield: 28.2 mg (77%); 97% ee (determined by chiral HPLC analysis after the product was purified).

30.5.6.4.2 Method 2: 1,3-Dipolar Cycloaddition Reactions between Azidomethyl Aryl Selenides and Alkynes (Click Reactions)

Aryl azidomethyl selenides 23 are easily prepared by reacting aryl chloromethyl selenides with sodium azide and 18-crown-6 in acetonitrile at room temperature (▶ Scheme 12).^[43] The azidomethyl aryl selenides can be used in copper-catalyzed 1,3-dipolar cycloaddition “click” reactions with terminal alkynes, in the presence of sodium ascorbate in aqueous media. 1-[(Arylselanyl)methyl]-1H-1,2,3-triazoles 24 are obtained, bearing a wide range of functional groups at the 4-position of the triazole, in good to high yields.

Scheme 12 Azidation of Alkynes Using Aryl Azidomethyl Selenides^[43]

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