A Simple Strategy for Incorporation, Protection, and Deprotection of ­Selenium Functionality

Abstract

Synthesis of di-2-cyanoethyl diselenide is reported for the first time. Using this reagent, incorporation and protection of ­selenium functionality can be achieved in one step with high yield, and the deprotection condition is mild, which allows alkylation ­simultaneously.

organoselenium compounds - selenium incorporation - selenol protection - deprotection

References and Notes

<A NAME="RS02106ST-1">1</A>

These authors have contributed equally to this publication.

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<A NAME="RS02106ST-12">12</A>

Di-2-cyanoethyl Diselenide ( 3). Solution of dioxane-EtOH (4:1, 100 mL) was injected into a flask containing selenium metal (7.9 g, 100 mmol; FW = 79) and NaBH₄ (2.7 g) under argon. After stirring the dark suspension for 1 h, 3-bromopropionitrile (12.4 mL, 150 mmol, 1.5 equiv; MW = 134, ρ = 1.62 g/mL) was added dropwise in an ice bath. The reaction was stirred for 1 h before it was poured into a beaker containing H₂O (400 mL). The suspension (yellow-orange) in the beaker was adjusted to pH 7 and then extracted with EtOAc (3 × 200 mL). The combined organic phases were washed with NaCl (sat., 100 mL) and then dried over MgSO₄ (s). After evaporation of the solvent under reduced pressure, the crude product was purified on silica gel column equilibrated with CH₂Cl₂-hexane (30:70). The gradient was run using CH₂Cl₂ in hexane (150 mL each, 30%, 40%, 50%, 60%, 70%, and 80%). The eluted product was light orange. The solvents were evaporated under reduced pressure (using rotary evaporator, do not use high vacuum) and co-evaporated with MeOH twice (2 × 30 mL). A light-orange product was obtained (9.65 g, 72% yield). ¹H NMR (300 MHz, CDCl₃): δ = 2.84 (t, J = 7.2 Hz, 2 H, CH₂Se), 3.04 (t, J = 7.2 Hz, 2 H, CH₂CN). ¹³C NMR (75 MHz, CDCl₃): δ = 18.65 (CH₂Se), 21.53 (CH₂CN), 118.27 (CN). HRMS (MALDI-FTMS): m/z [M (with ⁸⁰Se) + Na]⁺ calcd for C₆H₈N₂Se₂: 290.8916; found: 290.8912. When a large excess of NaBH₄ was used in the reaction, colorless di-2-cyanoethyl selenide was also isolated. ¹H NMR (300 MHz, CDCl₃). δ = 2.91 (t, J = 7.1 Hz, 2 H, CH₂Se), 3.53 (t, J = 7.1 Hz, 2 H, CH₂CN). ¹³C NMR (75 MHz, CDCl₃): δ = 21.03 (CH₂Se), 23.27 (CH₂CN), 117.42 (CN). HRMS (MALDI-FTMS): m/z [M with (⁸⁰Se + Na)]⁺ calcd for C₆H₈N₂Se: 210.9750; found: 210.9746.

<A NAME="RS02106ST-13">13</A>

Benzyl 2-Cyanoethyl Selenide ( 5a).
EtOH (5 mL) was added to NaBH₄ (317 mg) placed in an airtight flask under an argon balloon. The supernate of the mixture was added into a round-bottom flask (100 mL, on an ice bath) containing di-2-cyanoethyl diselenide (1.48 mL, 2.67 g, 10 mmol, ρ = 1.8 g/mL) under an argon balloon. After stirring for 5 min, the reaction turned colorless from light orange color. Benzyl chloride (0.75 mL, 821 mg, 6.5 mmol, ρ = 1.1 g/mL) was then injected into the reaction. After completion in 30 min (monitored on TLC, hexane-CH₂Cl₂ = 9:1; the product R _f = 0.61), H₂O (50 mL) was added to quench the reaction, and the pH was adjusted to 7 with 10% AcOH. The crude product was extracted three times with EtOAc (50 mL each time), and the organic phases were combined and dried over MgSO₄ (s). After removal of the solvent using rotary evaporator under reduced pressure, the crude product was purified by several preparative TLC plates (hexane-CH₂Cl₂ = 8:2). An oil product (1.412 g) was obtained (97% yield). ¹H NMR (CDCl₃): δ = 2.48 (t, J = 7.2 Hz, 2 H, CH₂Se), 2.55 (t, J = 7.2 Hz, 2 H, CH₂CN), 3.83 (s, 2 H, CH₂Ph), 7.18-7.32 (m, 5 H, arom. protons). ¹³C NMR (CDCl₃): δ = 17.19 (NCCH₂CH₂Se), 19.41 (CH₂CN), 27.80 (CH₂Ph), 118.91 (CN), 127.22 (p-ar.-C), 128.78 (o-ar.-C), 128.94 (m-ar.-C), 138.28 (ar. CCH₂Se). MS (ESI): m/z = 91 [benzyl]⁺, 169, 225 [M + H]⁺. HRMS (MALDI-FTMS): m/z [M with ⁸⁰Se]⁺ calcd for C₁₀H₁₁NSe: 225.0057; found: 225.0054.

<A NAME="RS02106ST-14">14</A>

2-Cyanoethyl 2-Phenylethyl Selenide ( 5b).
The synthesis (85% yield) is analogous to the synthesis of 5a. ¹H NMR (CDCl₃): δ = 2.62-2.81 (m, 4 H, SeCH₂CH₂CN), 2.94 (t, J = 7.4 Hz, 2 H, SeCH₂CH₂Ph), 3.04 (t, J = 7.4 Hz, 2 H, SeCH₂CH₂Ph), 7.18-7.37 (m, 5 H, arom.). ¹³C NMR (CDCl₃): δ = 17.57 (NCCH₂CH₂Se), 19.64 (CH₂CN), 25.95 (CH₂CH₂Ph), 36.94 (CH₂Ph), 118.87 (CN), 126.59 (p-ar.-C), 128.42 (o-ar.-C), 128.58 (m-ar.-C), 140.53 (ar. CCH₂Se). HRMS (MALDI-FTMS): m/z [M with ⁸⁰Se]⁺ calcd for C₁₁H₁₃NSe: 239.0213; found: 239.0209.

<A NAME="RS02106ST-15">15</A>

2-Cyanoethyl (1-Naphthyl)methyl Selenide ( 5c). The synthesis (81% yield) is analogous to the synthesis of 5a. ¹H NMR (CDCl₃): δ = 2.53 (t, J = 7.0 Hz, 2 H, NCCH₂CH₂Se), 2.66 (t, J = 7.0 Hz, 2 H, NCCH₂CH₂Se), 4.36 (s, 2 H, CH₂C₁₀H₇), 7.20-8.10 (m, 7 H, arom.). ¹³C NMR (CDCl₃): δ = 17.77 (NCCH₂CH₂Se), 19.48 (CH₂CN), 24.47 (CH₂C₁₀H₉), 118.91 (CN), 123.88, 125.20, 126.14, 126.22, 127.01, 128.39, 128.92, 130.96, 133.57, 134.15 (10 C, arom.). HRMS (ESI-TOF): m/z [M with (⁸⁰Se + Na)]⁺ calcd for C₁₄H₁₃NSe: 298.0105; found: 298.0099.

<A NAME="RS02106ST-16">16</A>

2-Cyanoethyl 3-(1,3-Dioxoisoindolin-2-yl)propyl Selenide ( 5d). The synthesis (97% yield) is analogous to the synthesis of 5a. In this reaction, mixture of MeOH and toluene (1:9) was used to dissolve N-(3-bromopropyl)phthalimide. ¹H NMR (CDCl₃): δ = 2.04-2.11 (m, 2 H, NCH₂CH₂CH₂Se), 2.69-2.86 (m, 6 H, NCH₂CH₂CH₂SeCH₂CH₂CN), 3.81 (t, J = 6.8 Hz, 2 H, NCH₂CH₂CH₂Se), 7.72-7.89 (m, 4 H, arom.). ¹³C NMR (CDCl₃): δ = 17.8 (NCCH₂CH₂Se), 20.1 (CH₂CN), 21.6 (NCH₂CH₂CH₂), 29.4 (NCH₂CH₂CH₂Se), 38.0 (NCH₂CH₂CH₂Se), 123.3 (CN), 132.4, 133.8 and 134.1 (C, arom.), 169.2 (C=O). ESI-MS: m/z [M with ⁸⁰Se]⁺ calcd for C₁₄H₁₄N₂O₂Se: 322.0221; found: 322.0218. When a large excess of NaBH₄ was used, reduction of the nitrile to the corresponding imine was also observed. ¹H NMR (CDCl₃): δ = 1.99-2.08 (m, 2 H, NCH₂CH₂CH₂Se), 2.66-2.78 (m, 6 H, NCH₂CH₂CH₂SeCH₂CH₂CH=NH), 3.51 (t, J = 6.8 Hz, 2 H, NCH₂CH₂CH₂Se), 4.05 (br, 1 H, NH), 5.76 (s, 1 H, SeCH₂CH₂CH=NH), 7.43-7.62 (m, 4 H, arom.). ESI-MS: m/z [M with ⁸⁰Se]⁺ calcd for C₁₄H₁₆N₂O₂Se: 324.0377; found: 324.0371.

<A NAME="RS02106ST-17">17</A>

Dibenzyl Selenide ( 7a).
A solution of K₂CO₃ (0.05 M in MeOH, 6 mL, 300 µmol, thoroughly purged with argon) was injected into a round-bottom flask containing benzyl (2-cyanoethyl) selenide (5a, 35.0 mg, 155 µmol) under argon, followed by injection of benzyl chloride (38.9 mg, 307 µmol, 2 equiv). When the reaction was completed over a few hours (monitored on analytical TLC, hexane-CH₂Cl₂ = 8:2), the solvent was evaporated under reduced pressure and the crude product was purified by preparative TLC (hexanes-CH₂Cl₂ = 7:3). An oil product was obtained (39.4 mg, 97% yield). ¹H NMR (CDCl₃): δ = 3.71 (s, 4 H, CH₂Ph), 7.19-7.32 (m, 10 H, arom. protons). ¹³C NMR (CDCl₃): δ = 27.2 (CH₂Ph), 127.2 (p-ar.-C), 128.7 (o-ar.-C), 128.9 (m-ar.-C), 138.2 (ar. CCH₂Se). MS (ESI): m/z = 91 [benzyl]⁺, 171, 260 and 262 [M⁺]. HRMS (MALDI-FTMS): m/z [M with ⁸⁰Se]⁺ calcd for C₁₄H₁₄Se: 262.0261; found: 262.0264.

<A NAME="RS02106ST-18">18</A>

Benzyl 2-Phenylethyl Selenide ( 7b). The synthesis (95% yield) is analogous to the synthesis of 7a. ¹H NMR (CDCl₃): δ = 2.74 (t, J = 7.3 Hz, 2 H, CH₂Se), 2.92 (t, J = 7.3 Hz, 2 H, CH₂CH₂Ph), 3.78 (s, 2 H, CH₂Ph), 7.17-7.36 (m, 10 H, arom.). ¹³C NMR (CDCl₃): δ = 26.1 (CH₂CH₂Ph), 27.9 (CH₂Ph), 38.0 (CH₂CH₂Ph), 126.3 and 126.7 (p-ar.-C), 128.4 and 128.7 (o-ar.-C), 129.6 and 129.9 (m-ar.-C), 139.4 and 141.2 (ar. CCH₂). HRMS (MALDI-FTMS): m/z [M with ⁸⁰Se]⁺ calcd for C₁₅H₁₆Se: 276.0417; found: 276.0419.

<A NAME="RS02106ST-19">19</A>

Benzyl (1-Naphthyl)methyl Selenide ( 7c). The synthesis (84% yield) is analogous to the synthesis of 7a. ¹H NMR (CDCl₃): δ = 3.71 (s, 2 H, CH₂C₁₀H₇), 4.12 (s, 2 H, CH₂Ph), 7.19-7.89 (m, 12 H, aromatic). ¹³C NMR (CDCl₃): δ = 25.30 (CH₂C₁₀H₇), 28.72 (CH₂Ph), 124.27, 125.48, 126.11, 126.29, 127.04, 127.10, 128.09, 128.37, 128.66, 128.88, 129.26, 129.34, 131.53, 134.35, 134.91, 139.36 (16 C, arom.). HRMS (MALDI-FTMS): m/z [M with ⁸⁰Se]⁺ calcd for C₁₈H₁₆Se: 312.0417; found: 312.0415.

<A NAME="RS02106ST-20">20</A>

Dibenzyl Diselenide ( 8a). A MeOH solution of K₂CO₃ (0.05 M, 6 mL, 300 µmol) was injected into a round-bottom flask containing benzyl (2-cyanoethyl) selenide (5a, 20.0 mg, 89 µmol), which was open to air. When the reaction was complete, (overnight; monitored by TLC, hexane-CH₂Cl₂ = 7:3, R _f = 0.38), the solvent was evaporated under reduced pressure and the crude product was purified by preparative TLC (hexane-CH₂Cl₂ = 6:4). A solid product was obtained (28.1 mg, 92% yield). ¹H NMR (CDCl₃): δ = 3.86 (s, 4 H, CH₂Ph), 7.23-7.38 (m, 10 H, arom. protons). ¹³C NMR (CDCl₃): δ = 32.58 (CH₂Ph), 127.09 (p-ar.-C), 128.43 (o-ar.-C), 129.01 (m-ar.-C), 138.18 (ar. CCH₂Se). MS (ESI): m/z = 91 [benzyl]⁺, 169, 181, 262, and 342 [M + H]⁺. HRMS (MALDI-FTMS): m/z [M with ⁸⁰Se]⁺ calcd for C₁₄H₁₄Se₂: 341.9426; found: 341.9428.

<A NAME="RS02106ST-21">21</A>

Di(phenylethyl) Diselenide ( 8b). ¹H NMR (CDCl₃): δ = 3.06 (t, J = 7.6 Hz, 4 H, CH₂Se), 3.18 (t, J = 7.6 Hz, 4 H, CH₂Ph), 7.22-7.37 (m, 10 H, arom.). ¹³C NMR (CDCl₃): δ = 30.72 (CH₂Se), 37.54 (CH₂Ph), 126.39 (p-ar.-C), 128.50 (o-ar.-C), 128.54 (m-ar.-C), 140.79 (ar. CCH₂Se). HRMS (MALDI-FTMS): m/z [M with ⁸⁰Se]⁺ calcd for C₁₆H₁₈Se₂: 369.9739; found: 369.9736.