Org. Synth. 2014, 91, 150-161
DOI: 10.15227/orgsyn.091.0150
Enantioselective Rhodium-Catalyzed [2+2+2] Cycloaddition of Pentenyl Isocyanate and 4-Ethynylanisole: Preparation and Use of Taddol-pyrrolidine Phosphoramidite
Submitted by Kevin M. Oberg, Timothy J. Martin, Mark Emil Oinen, Derek M. Dalton, Rebecca Keller Friedman, Jamie M. Neely, and Tomislav Rovis
*1
Checked by Yiyang Liu and Brian M. Stoltz
1. Procedure
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.
Taddol-pyrrolidine phosphoramidite. A 250-mL single-necked, round-bottomed flask equipped with an egg-shaped magnetic stir bar (12.7 x
25.4 mm) 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-bottomed
flask, a rubber septum is fitted, the reaction flask is put under an atmosphere of N2, and tetrahydrofuran (75 mL) (Note 2) is added via
syringe. 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 dropwise 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. Diethyl ether (50 mL) is then added, and the reaction mixture is filtered
through a medium-fritted funnel into a 250-mL round-bottomed flask. The solid residue in the reaction flask is washed with diethyl ether (2 x 25 mL) and
the filtrates are added into the round-bottomed flask. The ether is transferred to a 500-mL separatory funnel and washed with deionized water (50 mL) (Note 6). The organic layer is dried over MgSO4, vacuum-filtered through a 100 mL course-fritted filter funnel into a 250-mL round-bottomed flask
using a water aspirator, and the MgSO4 is rinsed with diethyl ether (2 x 10 mL). The filtrate is concentrated in vacuo using a rotovap,
and the off-white solid put under high vacuum for 30 min. An egg-shaped magnetic stir bar (12.7 x 25.4 mm) and EtOAc (5 mL) are added to the round-bottomed
flask containing the solid and a reflux condenser is attached. Using an oil bath, the mixture is heated to reflux with stirring and EtOAc (~20 mL) is added
dropwise until all of the solids dissolve. The stir bar is removed from the clear, slightly yellow solution. The round-bottomed flask 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 Büchner funnel (5 cm) with medium porosity filter paper to yield 1.78 g of Taddol-pyrrolidine phosphoramidite as white crystals (73%
yield) (Notes 7 and 8).
B. Pentenyl isocyanate. A 500-mL single-necked round-bottomed flask equipped with an egg-shaped magnetic stir bar (12.7 x 25.4 mm) is
flame-dried under vacuum. After cooling to 23 °C, a rubber septum is fitted to the round-bottomed flask and the flask is put under an atmosphere of N 2. Dichloromethane (50 mL) (Note 9) and 5-hexenoic acid (10.4 mL, 87.6 mmol) (Note 10) are added via syringe to the round-bottomed 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, 1.08 equiv) (Note 11) is added to the round-bottomed
flask via syringe over 5 min and the clear solution is stirred for 20 min. Diphenyl phosphoryl azide (20.4 mL, 94.6 mmol, 1.08 equiv) (Note 12) 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 hexanes (200 mL) (Note 13) is added. The reaction is stirred for 5 min 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-bottomed flask. The dichloromethane layer is returned to the separatory flask and the 250 mL Erlenmeyer flask is rinsed with hexanes (200 mL) 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-bottomed flask, which (without a septum) is placed into a 23 °C oil bath
that is heated to 50 °C for 3 h and then at 55 °C for 3 h. After cooling to ambient temperature, the solvent is removed in vacuo using a
23 °C bath. This yellow solution is transferred to a 25-mL round-bottomed flask, and the 1 L flask is rinsed with minimal hexanes, which are
transferred to the 25-mL round-bottomed flask. The 25-mL flask is concentrated in vacuo using a 23 °C bath (40 mmHg). The resultant yellow oil
is purified via vacuum distillation and the first clear fraction distilling at 63 °C (50 mmHg) is collected in a 25 mL round-bottomed flask cooled to
0 °C. Pentenyl isocyanate (4.34 g, 45%) is isolated as a clear liquid (Notes 14 and 15).
C. (R)-5-(4-Methoxyphenyl)-2,3,8,8a-tetrahydroindolizin-7(1H)-one. An oven-dried 250-mL round-bottomed flask equipped with a polygon magnetic
stir bar (6.4 x 25.4 mm) and an oven-dried reflux condenser with septum attached are loaded into an inert atmosphere (N2) glove box (Note 16).
Chlorobis(ethylene)rhodium(I) dimer (58 mg, 0.15 mmol, 0.005 equiv) (Note 17) and Taddol-pyrrolidine phosphoramidite (170 mg, 0.3 mmol, 0.01 equiv) are
added to the round-bottomed flask. The reflux condenser is attached, the apparatus is removed from the glove box, and toluene (110 mL) (Note 18) is added
via syringe resulting in a clear, gold solution. Toluene (5 mL) 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 19) and this solution is added to the reaction mixture via syringe. The vial is rinsed with toluene (5 mL), which is
added to the reaction vessel. Additional toluene (50 mL) 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 20) resulting in the isolation of 6.26 g (86%) of (R)-5-(4-methoxyphenyl)-2,3,8,8a-tetrahydroindolizin-7(1H)-one as a light brown solid (89% ee) (Notes 21, 22, and 23).
2. Notes
1.
(R,R)-Taddol was purchased from AK Scientific, Inc. and used as received.
2. Tetrahydrofuran (inhibitor-free, Chromasolv®, for HPLC, 99.9%) was purchased from Sigma-Aldrich, 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. If tap water or acidic water is used, degradation of the ligand can be observed by
31P NMR.
7. Physical characteristics of
Taddol-pyrrolidine phosphoramidite: [α]
25D = –157.8 (conc = 0.0106 g/mL, CHCl
3).
1H NMR
pdf(500 MHz, CDCl
3) δ: 0.29 (s, 3 H), 1.27 (s, 3 H), 1.68–1.94 (m, 4 H), 3.14–3.31 (m, 2 H), 3.32–3.49 (m,
2 H), 4.83 (d,
J = 8.5 Hz, 1 H), 5.21 (dd,
J = 8.4, 3.2 Hz, 1 H), 7.16–7.35 (m, 12 H), 7.41 (d,
J = 7.1 Hz, 2 H), 7.48 (d,
J = 7.1 Hz, 2 H), 7.60 (d,
J = 7.1 Hz, 2 H), 7.75 (d,
J = 7.1 Hz, 2 H).
13C NMR
pdf(126 MHz, CDCl
3) δ: 25.3,
26.0, 26.0, 27.5, 44.9, 45.0, 81.1, 81.2, 81.8, 82.2, 82.4, 82.5, 82.6, 111.7, 127.0, 127.1, 127.1, 127.2, 127.2, 127.4, 127.4, 127.6, 128.1, 128.7, 128.8,
129.0, 142.0, 142.3, 146.6, 146.9.
31P NMR
pdf(121 MHz, CDCl
3) δ: 137.1. IR (NaCl, Thin Film) 3058, 2967, 2869, 1493, 1446, 1035,
1003, 878, 737, 699 cm
-1. Mp = 214–216 °C (
EtOAc). HRMS (ESI)
m/z [C
35H
37NO
4P]
+
calcd 566.2455, found 566.2445. Anal. calcd for C
35H
36NO
4P: C, 74.32; H, 6.42; N, 2.48; O, 11.31; P, 5.48, found C, 74.33;
H, 6.71; N, 2.54; O, 11.09; P, 5.41.
8. On half scale (2.15 mmol Taddol), the yield was 68%.
9.
Dichloromethane (
methylene chloride, not stabilized, HPLC grade) was purchased from Fisher Scientific, degassed with Ar and passed through two columns of neutral alumina.
10.
5-Hexenoic acid was purchased from TCI and used as received.
11.
1,8-Diazabicyclo[5.4.0]undec-7-ene was purchased from AK Scientific, Inc. and distilled over
KOH before use.
12.
Diphenylphosphoryl azide was purchased from AK Scientific, Inc. and used as received.
13. Hexanes were distilled at ambient pressure over boiling chips.
14. Physical characteristics of
pentenyl isocyanate:
1H NMR
pdf(500 MHz, CDCl
3) δ: 1.66–1.77 (m, 2 H), 2.12–2.21 (m, 2
H), 3.32 (t,
J = 6.7 Hz, 2 H), 5.02 (ddt,
J = 10.2, 1.9, 1.2 Hz, 1 H), 5.07 (dq,
J = 17.1, 1.7 Hz, 1 H), 5.77 (ddt,
J = 17.0,
10.2, 6.7 Hz, 1 H).
13C NMR
pdf(126 MHz, CDCl
3) δ: 30.2, 30.5, 42.2, 115.9, 136.8. IR (NaCl, Thin Film) 3369, 2932, 2275, 1687,
1641, 1524, 1211, 911 cm
-1.
15. On half scale (43.8 mmol of
5-hexenoic acid), the yield of the product was 44%.
16. 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 the submitter has observed lower yields (15–25% lower) when
this catalyst is used on smaller scales. The phosphoramidite ligand is air stable and can be stored outside the glovebox, but the ligand is stored in the
glovebox for ease of reaction setup.
17.
Chlorobis(ethylene)rhodium(I) dimer was purchased from Strem, Inc., stored cold in an inert atmosphere glove box (N
2), and used as received.
18.
Toluene (Chromasolv®, for HPLC, 99.9%) was purchased from Sigma-Aldrich, degassed with Ar and passed through one column of neutral alumina and one
column of Q5 reactant.
19.
4-Ethynylanisole was purchased from AK Scientific, Inc. and used as received.
20. 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 x 150 mm
test tubes), product typically found in fractions 16-49. The first three fractions usually contain a small amount of impurity.
21. Physical characteristics of
(R)-5-(4-methoxyphenyl)-2,3,8,8a-tetrahydroindolizin-7(1H)-one: 89% ee by HPLC: Chiralcel ODH column, 90:10
Hex:iPrOH, 1 mL/min, 330nm, RT
major = 35.48 min, RT
minor = 41.75 min. [α]
25D = +637.3 (conc = 0.0084 g/mL
CHCl
3).
1H NMR
pdf(500 MHz, CDCl
3) δ: 1.71–2.06 (m, 3 H), 2.25– 2.51 (m, 3 H), 3.27 (dt,
J = 11.0,
7.1 Hz, 1 H), 3.50–3.58 (m, 1 H), 3.83 (s, 3 H), 3.98–4.09 (m, 1 H), 5.07 (s, 1 H), 6.91 (d,
J = 8.9 Hz, 2 H), 7.33 (d,
J = 8.8
Hz, 2 H).
13C NMR
pdf(126 MHz, CDCl
3) δ: 24.6, 31.7, 41.5, 49.5, 55.3, 58.7, 99.8, 113.8, 128.5, 129.2, 160.8, 162.6, 191.9. R
f = 0.16 (20:1
EtOAc:
MeOH). IR (NaCl, Thin Film) 2969, 2875, 1623, 1606, 1510, 1472, 1242, 1176, 1030 cm
-1. Mp = 129–132
°C. HRMS (ESI)
m/z [C
15H
18NO
2]
+ calcd 244.1332, found 244.1327. Anal. calcd for C
15H
17NO
2: C, 74.05; H, 7.04; N, 5.76; O, 13.15, found C, 74.08; H, 7.48; N, 5.80; O, 13.55.
22. On half scale (15 mmol of
pentenyl isocyanate), the product was obtained as a viscous dark brown oil (86% yield, 88% ee) that slowly solidified after
storing in –10 °C fridge for a week.
23.
(R)-5-(4-Methoxyphenyl)-2,3,8,8a-tetrahydroindolizin-7(1H)-one can be recrystallized from
EtOAc to yield light yellow crystals with 41% (98% ee)
recovery. mp = 133–135 °C (
EtOAc).
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should
be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National
Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines
for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee
the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in
any way to the procedures herein.
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 chromatography 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 is oxidized 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 more convenient. Additionally, if the
phosphoramidite is partially oxidized, recrystallization allows for isolation of the pure ligand without contamination with the oxidized ligand.
We have traditionally synthesized alkenyl isocyanates in one of two ways: conversion of the acyl azide to the isocyanate under reduced pressure
4
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 %.
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)
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)
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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 Professor 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 to Professor. He currently holds the John
K. Stille Chair in Chemistry.
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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 Colorado State University under the guidance of Professor Tomislav Rovis. His graduate research
focuses on the development of metal-catalyzed cycloadditions.
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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 under the direction of 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.
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Mark Emil Oinen graduated with a B.Sc. in chemistry from State University of New York college 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 Crestone Pharmaceuticals in Fort Collins, CO.
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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 University of Colorado Denver in 2007, he entered into his current position as a Ph. D. candidate at Colorado State
University where he investigates metal-catalyzed cycloadditions with Tomislav Rovis.
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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 Colorado, 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.
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Jamie M. Neely received 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.
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Yiyang Liu received his B.S. degree in Chemistry from Peking University in 2010 under the direction of Prof. Jianbo Wang and Prof. Yan
Zhang. He then moved to the California Institute of Technology and began his doctoral studies under the guidance of Prof. Brian Stoltz. His
graduate research focuses on chemical synthesis using renewable resources.
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