Org. Synth. 2005, 81, 147
DOI: 10.15227/orgsyn.081.0147
PRACTICAL SYNTHESIS OF NOVEL CHIRAL ALLENAMIDES: (R)-4-PHENYL-3-(1,2-PROPADIENYL)OXAZOLIDIN-2-ONE
[2-Oxazolidinone, 4-phenyl-3-(1,2-propadienyl)-, (4R)-]
Submitted by H. Xiong, M. R. Tracey, T. Grebe, J. A. Mulder, and R. P. Hsung
1.
Checked by Peter Wipf and Jennifer Smotryski.
1. Procedure
A. (R)-4-Phenyl-3-(2-propynyl)oxazolidin-2-one (2). A flame-dried, 500-mL, round-bottomed flask equipped with a magnetic stirbar and a rubber septum fitted with a nitrogen inlet is charged with 9.90 g (61 mmol) of (R)-4-phenyl-2-oxazolidinone (Note 1) and 200 mL of anhydrous tetrahydrofuran (THF) under a nitrogen atmosphere (Note 2). Sodium hydride (NaH) (2.90 g, 60% w/w in mineral oil, 1.20 equiv, 73 mmol) is added in small portions (Note 3), and the resulting white slush is stirred for 1 hr at room temperature before carefully adding 8.00 mL of a solution of propargyl bromide in toluene (80% w/w in toluene, 72 mmol, 1.18 equiv) (Note 4) dropwise over ca. 10 min via syringe. Precipitation of sodium bromide is observed and does not affect the progress of the reaction. The reaction mixture is stirred at room temperature for 24 hr and then concentrated by rotary evaporation under reduced pressure. The residue is dissolved in 100 mL of anhydrous ether and filtered through a small bed of Celite washing with 1:1 ethyl acetate-hexane. The filtrate is concentrated by rotary evaporation, and the resulting residue is purified using silica gel column chromatography (gradient eluent with 0-33% ethyl acetate-hexane) to give 5.71-6.09 g (47-50%) of the desired propargyl amide 2 as a lightly yellow-colored oil (Note 5).
B. (R)-4-Phenyl-3-(1,2-propadienyl)-2-oxazolidinone (3). A flame-dried, 500-mL, round-bottomed flask equipped with a magnetic stirbar and a rubber septum fitted with a nitrogen inlet is charged with a solution of 6.67 g (33 mmol) of propargyl amide 2 in 300 mL of anhydrous THF (Note 2). Potassium tert-butoxide (1.26 g, 11 mmol, 0.33 equiv) (Notes 6, 7) is added in portions to the reaction mixture over ca. 10 min. The reaction mixture is stirred at room temperature for 24 hr and the progress of the reaction is monitored by TLC (elution with 50% ethyl acetate-hexane) and 1H NMR analysis. Upon completion of the reaction, the solvent is removed by rotary evaporation under reduced pressure. The resulting crude residue is dissolved in 50 mL of ethyl acetate and vacuum filtered through a small bed of silica gel. The solids are washed with two 40-mL portions of 25-50% ethyl acetate-hexane, and the filtrate is then concentrated by rotary evaporation. The residue is purified using silica gel column chromatography (gradient elution with 0% to 25% ethyl acetate-hexanes) to give 1.41-1.59 g (38-41%) of the desired allenamide 3 as a yellow brownish-red oil (Note 8).
2. Notes
1.
(R)-4-Phenyl-2-oxazolidinone was purchased from Sigma-Aldrich or Urquima, S.A. Arnau de Vilanove, Barcelona, Spain and used as received.
2.
Anhydrous THF was freshly distilled from sodium/benzophenone under
nitrogen.
3.
Caution: evolution of large amount of H2 gas.
NaH was obtained from Sigma-Aldrich and used as received. NaH free of oil can also be used with no difference in yield and was prepared via four cycles of washing and decanting (via pipette) with anhydrous
pentane.
4.
Propargyl bromide was obtained as an 80% w/w solution in toluene from Sigma-Aldrich.
5.
The submitters report obtaining the product in
66% yield prior to purification at 0.050 mole-scale and suggest that the purification step is not necessary because in most cases simple filtration through a small bed of Celite or silica gel provided the desired
propargyl amide with high purity as determined by GC analysis. Specifically, GC analysis of
propargyl amide 2 shows its purify to be 98.2% prior to column chromatography, and 98.5% after chromatography. After column chromatography, the submitters obtained
6.40 g (
52%) of the desired amide. The amide displays the following physical properties: R
f = 0.49 (
50% EtOAc in hexane);
[α]D20 148.8 (c 10.2, EtOH);
1H NMR (300 MHz, CDCl
3) δ: 2.25 (t, 1H,
J = 2.4 Hz), 3.35 (dd, 1H,
J = 2.4, 17.7), 4.12 (dd, 1H,
J = 7.8, 8.7), 4.36 (dd, 1H,
J = 2.4, 17.7), 4.65 (t, 1H,
J = 8.7), 4.95 (dd, 1H,
J = 7.8, 8.7, 7.32-7.44 (m, 5H);
13C NMR (75 MHz, CDCl
3) δ: 32.0, 59.0, 70.0, 73.4, 76.6, 127.3, 129.3, 129.4, 136.6, 157.8; IR (neat) cm
−1: 3285, 2913, 2100, 1733, 1494, 1177, 860; mass spectrum (EI): m/e (%relative intensity) 201 (20) M
+, 156 (51), 143 (24), 124 (30), 116 (66), 104 (100), 91 (22), 77 (21); m/e calcd for C
12H
12NO
2: 202.086; found 202.0871.
6.
Potassium tert-butoxide was obtained from Sigma-Aldrich and used as received. Alternatively, equivalent results were obtained using
t-BuOK that was prepared from
potassium metal and anhydrous
tert-butyl alcohol (t-BuOH) followed by removal of excess
t-BuOH. In this case, the molecular weight of
t-BuOK was calculated based on a 1:1 ratio of
t-BuOK to
t-BuOH (i.e., 186.34 for C
8H
19O
2K).
7.
The submitters report that equivalent results were obtained using between 0.20-0.35 equiv of
t-BuOK.
8.
The submitters report obtaining the allenamide in
63% yield on this scale with its purity determined by GC analysis to be between 94%-96% in different runs. The lower yield obtained by the checkers may be explained by partial decomposition of product during the chromatographic purification on standard (40-60 nm) silica gel. The physical properties of
3 are as follows: R
f = 0.59 (
50% ethyl acetate-hexane);
[α]D20 −156.4(c 0.225, CHCl3);
1H NMR
pdf (500 MHz, CDCl
3)) δ: 4.14 (dd, 1H,
J = 5.9, 9.8), 4.69 (t, 1H,
J = 9.0), 4.87 (dd, 1H,
J = 6.4, 9.5), 4.88 (dd, 1H,
J = 6.4, 9.5), 5.16 (dd, 1H,
J = 5.9, 9.8), 6.79 (t, 1H,
J = 6.4), 7.23 – 7.37 (m, 5H);
13C NMR (75 MHz, CDCl
3) δ: 59.0, 70.6, 87.7, 95.6, 126.5, 128.7. 129.0, 138.4, 155.5, 201.9; IR (neat) cm
−1 3063, 3035, 2979, 1963, 1767, 1494, 1462, 1216, 966, 911, 881; mass spectrum (EI): m/e (%relative intensity) 201 (17) M
+, 156 (100), 129 (17), 115 (20), 104 (54), 91 (17), 77 (17); m/e calcd for C
12H
11NO
2 201.0790, found 201.0784.
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
A. Preparation.
The level of purity during preparations of allenamides was unambiguously established using GC analysis for both the propargyl amide intermediates and the allenamides. The level of optical purity was established based on optical purity of the chiral auxiliaries from commercial sources. The [α]D20 values for the commercial (R)-2-phenyloxazolidinone and (S)-2-phenyloxazolidinone that were used for this preparation are −52.33 (c 2.0, CHCl3) and +52.95 (2.0, CHCl3), respectively. Based on the known [α]D20 values for (R)-2-phenyloxazolidinone and (S)-2-phenyloxazolidinone from Aldrich (−48.0 (c 2.0, CHCl3) and +48.0(c 2.0, CHCl3), respectively), the ee or optical integrity of these two enantiomeric auxiliaries should be very high. Since it is not likely to severely erode the ee of the auxiliary under the rather mild reaction conditions described in these two procedures, the level of ee for propargyl amide (R)-2 and allenamide (R)-3 should be comparable to that of the starting (R)-2-phenyloxazolidinone.
Furthermore, using (S)-2-phenyloxazolidinone led to the propargyl amide (S)-2a that has an opposite optical rotation of + 157.97 (c 10.0, EtOH). After based-induced isomerization, the allenamide (S)-3a also possesses an opposite optical rotation of + 157.13 (c 10.0, CH2Cl2).
B. Applications.
- Stereoselective inverse-demand hetero (4 + 2) cycloadditions. A Chiral Template for C-Aryl Glycoside Synthesis. Chiral allenamides2,3,4 had been used in highly stereoselective inverse-demand hetero (4 + 2) cycloaddition reactions with heterodienes.5 These reactions lead to stereoselective synthesis of highly functionalized pyranyl heterocycles. Further elaboration of these cycloadducts provides a unique entry to C-aryl-glycosides and pyranyl structures that are common in other natural products (Scheme 1).
- Highly stereoselective [4 + 3] oxyallyl cycloadditions.
An endo-Selective Sequential Epoxidation-Oxyallyl Cycloaddition and the First Nitrogen-Stabilized Oxyallyl Cations.
Epoxidations of chiral allenamides lead to chiral nitrogen-stabilized oxyallyl catioins that undergo highly stereoselective (4 + 3) cycloaddition reactions with electron-rich dienes.6 These are the first examples of epoxidations of allenes, and the first examples of chiral nitrogen-stabilized oxyallyl cations. Further elaboration of the cycloadducts leads to interesting chiral amino alcohols that can be useful as ligands in asymmetric catalysis (Scheme 2).
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
(R)-4-Phenyl-2-oxazolidinone:
2-Oxazolidinone, 4-phenyl-, (4R)-; (90319-52-1).
Sodium hydride:
Sodium hydride (NaH); (7646-69-7).
Propargyl bromide:
1-Propyne, 3-bromo-; (106-96-7).
R-4-Phenyl-3-(2-propynyl)-2-oxazolidinone:
2-Oxazolidinone, 4-phenyl-3-(2- propynyl); (4R)-; (256382-74-8).
R-4-Phenyl-3-(1,2-propadieny)-2-oxazolidinone:
2-Oxazolidinone, 4-phenyl-3-(1,2- propadienyl)-, (4R)-; (256382-50-0).
Potassium tert-butoxide:
2-Propanol, 2-methyl-, potassium salt; (865-47-4).
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