Enantioselective Rhodium-Catalyzed [2+2+2] Cycloaddition of Pentenyl Isocyanate and 4-Ethynylanisole: Preparation and Use of Taddolpyrrolidine Phosphoramidite

Abstract

Caution, alkyl acyl azides can rapidly decompose with heat to release large amounts of nitrogen. Care should be taken during handling: do not attempt to convert neat and avoid handling neat.

1. Procedure

A. Taddol-pyrrolidine phosphoramidite

A 250 mL single-necked round bottom flask equipped with a magnetic stir bar is flame dried under vacuum. After cooling to 23 °C, (R,R)-Taddol (2.0 g, 4.29 mmol) (Note 1) is added to the round bottom, a rubber septum is fitted, the reaction flask is put under an atmosphere of Ar, and tetrahydrofuran (75 mL) (Note 2) is added via syringe to the round bottom. To this clear, colorless solution, triethylamine (2.4 mL, 17.2 mmol, 4 equiv) (Note 3) is added via syringe resulting in a clear solution with a slight yellow color. The reaction mixture is cooled to 0 °C with an ice bath and phosphorous trichloride (0.39 mL, 4.5 mmol, 1.05 equiv) (Note 4) is added drop wise over 2 min via syringe resulting in a white suspension. The ice bath is removed, the reaction is allowed to warm to 23 °C and stirred for 1 h. The reaction mixture is cooled to 0 °C with an ice bath, and pyrrolidine (1.8 mL, 21.4 mmol, 5 equiv) (Note 5) is added via syringe. The ice bath is removed, the reaction is allowed to warm to 23 °C and stir for 1 h. 50 mL Et₂O is then added, and the reaction mixture is filtered through a medium fritted funnel into a 250 mL round bottom flask. The solid residue in the reaction flask is washed an additional two times with 25 mL Et₂O and filtered into the round bottom flask. The filtrate is transferred to a 500 mL separatory funnel and washed with 50 mL of deionized water (Note 6). The organic layer is dried over MgSO₄, vacuum filtered through a course fritted filter funnel into a 250 mL round bottom using a water aspirator, and the MgSO₄ is rinsed twice with 10 mL Et₂O. The filtrate is concentrated in vacuo using a rotovap, and the off-white solid put under high vacuum for 30 min. A magnetic stir bar and 5 mL EtOAc are added to the round bottom containing the solid and a reflux condenser is attached. Using an oil bath, the mixture is heated to reflux with stirring and EtOAc is added dropwise until all the solid dissolves (~20 mL). The stir bar is removed from the clear, slightly yellow solution. The round bottom is allowed to cool slowly in the oil bath to 23 °C, placed in a −10 °C fridge for 12 h, and then placed in a −24 °C freezer for 12 h. The solid is collected with a Buchner funnel (5 cm) with medium porosity filter paper to yield 1.58 g of Taddol-pyrrolidine phosphoramidite as white crystals (65 % yield) (Note 7).

B. Pentenyl isocyanate

A 500 mL single-necked round bottom flask equipped with a magnetic stir bar is flame dried under vacuum. After cooling to 23 °C, a rubber septum is fitted to the round bottom flask and the flask is put under an atmosphere of Ar. Dichloromethane (50 mL) (Note 8) and 5-hexenoic acid (10.4 mL, 87.6 mmol) (Note 9) are added via syringe to the round bottom flask and the flask is cooled to 0 °C with an ice bath. 1,8-diazabicylo[5.4.0]undec-7-ene (14.2 mL, 94.6 mmol, 1.1 equiv) (Note 10) is added to the round bottom via syringe over 5 minutes and the clear solution is stirred for 20 minutes. Diphenyl phosphoryl azide (20.4 mL, 94.6 mmol, 1.1 equiv) (Note 11) is added over 5 min via syringe resulting in a clear, yellow solution. The reaction mixture is stirred for 3 h at 0 °C. The ice bath is removed, the septum is removed, and 200 mL hexanes (Note 12) is added. The reaction is stirred for 5 minutes and transferred to a 500 mL separatory funnel. After the layers separate, the lower, yellow dichloromethane layer is collected in a 250 mL Erlenmeyer flask and the upper, cloudy hexane layer is transferred to a 1 L round bottom flask. The dichloromethane layer is returned to the separatory flask and the 250 mL Erlenmeyer flask is rinsed with 200 mL hexanes and transferred to the separatory funnel. The dichloromethane layer is extracted with hexanes. The lower dichloromethane layer is collected in the 250 mL Erlenmeyer flask and the cloudy hexane layer is transferred to the 1 L round bottom flask. The 1 L round bottom flask (without a septum) is put into a 23 °C oil bath that is heated to 50 °C for 3 h and then at 55 °C for 3 h (Note 13). After conversion is complete, the solvent is removed in vacuo using a 23 °C bath, resulting in a yellow solution. This solution is transferred to a 25 mL round bottom flask and the 1 L flask is rinsed with minimal hexanes and transferred to the 25 mL round bottom flask. The 25 mL flask is concentrated in vacuo using a 23 °C bath. The resultant yellow oil is purified via vacuum distillation and the first clear fraction distilling at 63 °C (50 torr) is collected in a 25 ml round bottom flask cooled to 0 °C. This yields 4.93 g of pentenyl isocyanate as a clear liquid (51 % yield) (Note 14).

C. (R)-5-(4-methoxyphenyl)-2,3,8,8a-tetrahydroindolizin-7(1H)-one

An oven dried 250 mL round bottom flask equipped with a magnetic stir bar and an oven dried reflux condenser with septum attached are loaded into an inert atmosphere (Ar) glove box (Note 15). Chlorobis(ethylene)rhodium(I) dimer (58 mg, 0.15 mmol, 0.005 equiv) (Note 16) and Taddol-pyrrolidine phosphoramidite (170 mg, 0.3 mmol, 0.01 equiv) are added to the round bottom. The reflux condenser is attached, the apparatus is removed from the glove box, and 110 mL PhMe (Note 17) is added via syringe resulting in a clear, gold solution. 5 mL PhMe is added to a vial containing pentenyl isocyanate (3.33 g, 30 mmol) and 4-ethynylanisole (6.0 g, 45 mmol, 1.5 equiv) (Note 18) and this solution is added to the reaction mixture via syringe. The vial is rinsed with 5 mL PhMe, added to the reaction vessel, and another 50 mL PhMe is added to the reaction mixture resulting in a crimson solution. The reaction mixture is heated to 110 °C in an oil bath for 36 h resulting in a dark brown solution. The reaction mixture is concentrated in vacuo, and the crude reaction mixture is purified via flash chromatography (Note 19) resulting in 5.11 g (R)-5-(4-methoxyphenyl)-2,3,8,8a-tetrahydroindolizin-7(1H)-one as a light brown solid (70% yield, 90% ee) (Note 20,21).

2. Notes

1. (R,R)-Taddol was purchased from AK Scientific, Inc. and used as received.

2. Tetrahydrofuran was degassed with Ar and passed through two columns of neutral alumina.

3. Triethylamine was purchased from Sigma-Aldrich and distilled over KOH before use.

4. Phosphorous trichloride was purchased from Sigma-Aldrich and distilled before use.

5. Pyrrolidine was purchased from Sigma-Aldrich and distilled over KOH before use.

6. Use of deionized water is necessary. Degradation of ligand is observed by ³¹P NMR if tap water or acidic water is used.

7. Physical characteristics of Taddol-pyrrolidine phosphoramidite: [α]²⁰_D = -145.5 (conc = 0.0106 g/mL, CHCl₃). ¹H NMR (300 MHz, CDCl₃) δ 7.74 (dm, J = 6.9 Hz, 2H), 7.60 (dm, J = 7.2 Hz, 2H), 7.48 (dm, J = 7.2 Hz, 2H), 7.41 (dm, J = 7.2 Hz, 2H), 7.34 - 7.15 (m, 12 H), 5.20 (dd, J = 8.4, 3.3 Hz, 1H), 4.82 (d, J = 8.4 Hz, 1H), 3.44 - 3.34 (m, 2H), 3.26 - 3.17 (m, 2H), 1.87 - 1.73 (m, 4H), 1.26 (s, 3H), 0.28 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 146.9, 146.6, 142.2, 142.0, 129.0, 128.8, 128.7, 128.0, 127.6, 127.4, 127.2, 127.1, 127.1, 127.0, 111.7, 82.6, 82.5, 82.4, 82.2, 81.8, 81.2, 45.1, 44.9, 27.5, 26.0, 25.9, 25.3. ³¹P NMR (121 MHz, CDCl₃) δ 137.7. IR (NaCl, Thin Film) 3060, 2969, 2883, 1492, 1447, 1035, 737. Mp = 215-217 °C (EtOAc). HRMS (ESI) m/z [C₃₅H₃₇NO₄P] calcd 566.2455, found 566.2454. Anal. calcd for C₃₅H₃₆NO₄P: C, 74.32; H, 6.42; N, 2.48; O, 11.31; P, 5.48, found C, 74.29; H, 6.48; N, 2.57; O, 11.58; P, 4.94.

8. Dichloromethane was degassed with Ar and passed through two columns of neutral alumina.

9. 5-Hexenoic acid was purchased from TCI and used as received.

10. 1,8-Diazabicyclo[5.4.0]undec-7-ene was purchased from AK Scientific, Inc. and distilled over KOH before use.

11. Diphenyl phosphoryl azide was purchased from AK Scientific, Inc. and used as received.

12. Hexanes were distilled at ambient pressure over boiling chips.

13. Conversion can be monitored by ¹H NMR (2.35 (t, 2H) shifts to 3.32 (t, 2H)) or IR (1720 shifts to 2171) for completion. Physical characteristics for acyl azide: ¹H NMR (300 MHz, CDCl₃) δ 5.76 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.03 (dm, J = 17.1 Hz, 1H), 5.00 (dm, J = 10.2 Hz, 1H), 2.35 (t, J = 7.5 Hz, 2H), 2.10 (dt, J = 7.2, 7.2 Hz, 2H), 1.73 (tt, J = 7.5, 7.2 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 180.5, 137.2, 115.7, 36.0, 32.8, 23.7. R_f = 0.52 (20:1 Hex:EtOAc). IR (NaCl, Thin Film) 2360, 2138, 1720, 1369, 1161.

14. Physical characteristics of pentenyl isocyanate: ¹H NMR (300 MHz, CDCl₃) δ 5.77 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.07 (dm, J = 17.1 Hz, 1H), 5.03 (dm, J = 10.2 Hz, 1H), 3.32 (t, J = 6.6 Hz, 2H), 2.16 (dt, J = 6.9, 6.9 Hz, 2H), 1.71 (tt, J = 6.9, 6.9 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 136.7, 121.9, 115.6, 42.0, 30.4, 30.1. IR (NaCl, Thin Film) 2927, 2171, 1690, 1489, 1183, 966.

15. The use of a glove box is for simplicity of set up due to the air sensitive nature of chlorobis(ethylene)rhodium(I) dimer. Use of standard Schlenk techniques in place of a glove box should provide similar results if the chlorobis(ethylene)rhodium(I) dimer is of high quality. Chlorobis(cyclooctadiene)rhodium(I) dimer may be used as an air stable alternative, but we observe lower yields (15-25% lower) when this catalyst is used on smaller scale. The phosphoramidite ligand is air stable and can be stored outside the glovebox, but is stored in the glovebox for ease of reaction setup.

16. Chlorobis(ethylene)rhodium(I) dimer was purchased from Strem, Inc., stored cold in an inert atmosphere glove box (Ar), and used as received.

17. Toluene was degassed with Ar and passed through one column of neutral alumina and one column of Q5 reactant.

18. 4-Ethynylanisole was purchased from AK Scientific, Inc. and used as received.

19. Column diameter: 6 cm, silica: 140 g (Silicycle, Inc. silica 60 (230-400 mesh)), eluant: 2.5 L (20:1 EtOAc:MeOH), fraction size: 50 mL (25 × 150 mm test tubes), product typically found in fractions 16-49.

20. Physical characteristics of (R)-5-(4-methoxyphenyl)-2,3,8,8atetrahydroindolizin-7(1H)-one: 90% ee by HPLC: Chiralcel ODH column, 90:10 Hex:iPrOH, 1 mL/min, 330nm, RT_major = 27.72 min, RT_minor = 33.82 min. [α]²⁰_D = +592.9 (conc = 0.0084 g/mL CHCl₃ ). ¹H NMR (300 MHz, CDCl₃) δ 7.34 (dm, J = 8.7 Hz, 2H), 6.92 (dm, J = 8.7 Hz, 2H), 5.08 (s, 1H), 4.05 (dddd, J = 13.5, 6.9, 6.9, 6.9 Hz, 1H), 3.84 (s, 3H), 3.55 (ddd, J = 11.4, 7.2, 5.7 Hz, 1H), 3.27 (ddd, J = 10.8, 7.2, 7.2 Hz, 1H), 2.53 - 2.25 (m, 3H), 2.07 - 1.71 (m, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 191.9, 162.7, 160.8, 129.2, 128.4, 113.8, 99.7, 58.6, 55.3, 49.5, 41.4, 31.6, 24.6. R_f = 0.16 (20:1 EtOAc:MeOH). IR (NaCl, Thin Film) 2967, 2878, 1624, 1507, 1245, 1030. HRMS (ESI) m/z [C₁₅H₁₈NO₂]⁺ calcd 244.1332, found 244.1330. Anal. calcd for C₁₅H₁₇NO₂: C, 74.05; H, 7.04; N, 5.76; O, 13.15, found C, 73.99; H, 7.10; N, 5.80; O, 13.28.

21. (R)-5-(4-methoxyphenyl)-2,3,8,8a-tetrahydroindolizin-7(1H)-one can be recrystalized from EtOAc to yield light yellow crystals. 86% recovery, 96% ee, mp = 126-129 °C (EtOAc).

Waste Disposal Information

All hazardous materials should be handled and disposed of in accordance with “Prudent Practices in the Laboratory”; National Academy Press; Washington, DC, 1995.

3. Discussion

The use of chiral phosphoramidites is prevalent in organic chemistry.² In our lab, we have found phosphoramidites to be excellent ligands for many of our rhodium-catalyzed syntheses of nitrogen-containing heterocycles.³ This procedure describes an improved synthesis of Taddol-pyrrolidine phosphoramidite, a column free synthesis of pentenyl isocyanate, and use of these compounds in the enantioselective rhodium-catalyzed [2+2+2] cycloaddition of pentenyl isocyanate and 4-ethynylanisole.

Our first synthesis of Taddol-pyrrolidine phosphoramidite used column chromatography for purification of the phosphoramidite.⁴ We have observed that the phosphoramidite oxidizes under acidic conditions and purification via column chromatography can result in partially oxidized ligand. Recrystallization avoids use of acidic silica for purification and makes the overall isolation of the ligand easier. Additionally, if the phosphoramidite is partially oxidized, recrystallization allows for isolation of the pure ligand without contamination from the oxidized ligand.

We have traditionally synthesized alkenyl isocyanates in one of two ways: conversion of the acyl azide to the isocyanate under reduced pressure⁴ and column chromatography of the acyl azide followed by neat conversion.⁵ These methods work well for small scale, but on larger scale, these approaches can potentially be dangerous if proper precautions are not observed. In order to make the synthesis more accessible, we developed a method where the acyl azide is not purified via column chromatography or isolated neat. The choice of 1,8-diazabicyclo[5.4.0]undec-7-ene as the base allows for good conversion to the acyl azide and makes purification by distillation easier due to its high boiling point.

The enantioselective rhodium-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and alkynes has been extensively investigated in our lab.⁶ This procedure demonstrates the scalability of the reaction and the ability to lower catalyst loadings to 1 mol %.

Biography

Tomislav Rovis was born in Zagreb in the former Yugoslavia but was raised in Southern Ontario, Canada. Following his undergraduate studies at the University of Toronto, he earned his Ph. D. degree at the same institute in 1998 under the direction of Prof essor Mark Lautens. From 1998-2000, he was an NSERC postdoctoral fellow at Harvard University with Professor David A. Evans. In 2000, he began his independent career at Colorado State University and was promoted in 2005 to Associate Professor and in 2008 t o Professor. He currently holds the John K. Stille Chair in Chemistry.

Kevin M. Oberg received his B . A . from Gustavus Adolphus College , where he worked under the supervision of Professor Brian A. O'Brien. He is now pursuing his graduate studies at C olorado State University under the guidance of Professor Tomislav Rovis. His graduate research focuses on the development of metal-catalyzed cycloadditions.

Timothy J. Martin received his B. Sc. in chemistry from University of Delaware . He received his Ph. D. in 2011 from University of North Carolina-Chapel Hill unde r Professor Michael Crimmins. His graduate studies were focused on the synthesis of Amphidinol 3 and his post-doctoral studies focused on nitrogen heterocycle synthesis using rhodium catalysis.

Mark Emil Oinen graduated with a B.Sc. in chemistry from State University of New York colleg e at Brockport 2005, under the supervision of Professor Margaret Logan. He received his M. Sc. In Chemistry in 2010 from the Colorado State University under the guidance of Professor Tomislav Rovis. Mark is currently an associate research scientist for Cre stone Pharmaceutials in Fort Collins, CO .

Derek M. Dalton was born in Aurora, Colorado in 1981. After earning a B. A. (Religion) at the Colorado College in 2004 and a B. Sc. (Chemistry) at the Univer s i ty of Colorado Denver in 2007, he entered into h is current position as a Ph . D. candidate at Colorado State University where he investigates metal-catalyzed cycloadditions with Tomislav Rovis .

Rebecca Keller Friedman (born 1983) graduated with a B.A. in chemistry from Washington University in St. Louis in 2005. She received her Ph. D. in 2010 from Colorado State University under the guidance of Tomislav Rovis working on the development of rhodium-catalyzed [2+2+2] and [4+2+2] cyclizations. She then joined the labs of Xiang Wang (University of Col orado, Boulder) as a post-doctoral researcher, focusing on the method development of gold-catalyzed [3,3]-rearrangements of indole derivatives. She is currently working as a scientific analyst for Stratfor: Global Intelligence .

Jamie M. Neely receiv ed her B. Sc. in chemistry from the University of Missouri in Columbia, where she worked under the supervision of Professor Timothy Glass. She began her graduate studies in 2008 at Colorado State University under the advisement of Professor Tomislav Rovis . Her current research focuses on the synthesis of heterocycles via C-H activation.

Appendix

Chemical Abstracts Nomenclature; (Registry Number)

(R,R)-Taddol: 1,3-Dioxolane-4,5-dimethanol, 2,2-dimethyl-a4,a4, a5,aα-tetraphenyl-, (4R,5R)-; (93379-48-7)

Triethylamine: Ethanamine, N,N-diethyl-; (121-44-8)

Phosphorous trichloride; (7719-12-2)

Pyrrolidine; (123-75-1)

Taddol-pyrrolidine phosphoramidite: Pyrrolidine, 1-[(3aR,8aR)-tetrahydro-2,2-dimethyl-4,4,8,8-tetraphenyl-1,3-dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-yl]-; (913706-72-6) 5-Hexenoic acid; (1577-22-6) 1-8-Diazabicyclo[5.4.0]undec-7-ene: Pyrimido[1,2-a]azepine, 2,3,4,6,7,8,9,10-octahydro-; (6674-22-2)

Diphenyl phosphoryl azide: Phosphorazidic acid, diphenyl ester; (26386-88- 9)

4-Pentenyl isocyanate: 1-Pentene, 5-isocyanato-; (2487-98-1)

Chlorobis(ethylene)rhodium(I) dimer: Rhodium, di-μ-chlorotetrakis(η2-ethene)di-; (12081-16-2)

4-Ethynylanisole: Benzene, 1-ethynyl-4-methoxy-; (768-60-5) (R)-5-(4-methoxyphenyl)-2,3,8,8a-tetrahydroindolizin-7(1H)-one: 7(1H)-Indolizinone, 2,3,8,8a-tetrahydro-5-(4-methoxyphenyl)-,(8aR)-; (913626-94-5)