Organic Syntheses, Vol. 83, p.5 (2006).
) can be prepared by the following procedure (not attempted by the checkers): A flame-dried 2-L, one-necked, round-bottomed flask
, equipped with an egg-shaped magnetic stirring bar, a rubber septum and an internal thermocouple probe
is purged with argon
. The flask is then charged with 1 L of anhydrous dichloromethane
. The septum is removed and acetone oxime (16.56 g, 227 mmol)
is added quickly in one portion and the flask is sealed and purged again with argon
. Freshly distilled triethylamine (31.6 mL, 227 mmol)
is added via a syringe and the resulting colorless solution is cooled to −78 °C (internal temperature) with an acetone
/dry ice bath (approximately 30 min are needed to reach this temperature). Freshly distilled, colorless chlorodiphenylphosphine (42 mL, 227 mmol)
is added dropwise (2 mL/min) via a syringe at such a rate that the internal temperature does not exceed −70 °C. After the addition is complete, the resulting milky solution is stirred 15 min at −78 °C under argon
. The cooling bath is removed, and the solution is allowed to warm to room temperature over a period of 1.5 h and stirred 1 h at that temperature. The milky solution becomes clear. The solvent is removed under reduced pressure and the resulting off-white to yellow solid is dried under vacuum for 12 h. The residue is dissolved in acetone (200 mL)
and dried under reduced pressure. This last step is repeated once again. (This step makes the removal of the solid from the flask easier. Furthermore, the solid can be ground to a finer powder, which facilitates the next step. This step can be avoided but problems may occur, such as the formation of a gummy yellow solid during the addition to the aqueous ammonium hydroxide
solution. This problem can be related to the presence of dichloromethane
in the solid. Heating the mixture with a heat gun to dissolve everything can solve this problem, but lower yields and side-products are obtained.) The solid is removed from the flask and ground to a powder using a mortar and pestle. The powder is added in one portion into an Erlenmeyer flask
containing a stirring solution (magnetic stirring bar
) of concentrated aqueous ammonium hydroxide (660 mL)
and distilled water (330 mL). The mixture is usually heterogeneous and the precipitate is a white solid. Sometimes the solid added dissolves rapidly to form a clear yellow solution and, after few seconds, a white solid starts to precipitate. The heterogeneous mixture is stirred for 45 min and 1
is obtained as a white solid by filtration through a sintered glass funnel. The aqueous filtrate is extracted with dichloromethane (3 × 600 mL)
. The combined extracts are dried over Na2SO4
, filtered and evaporated under reduced pressure. The white solid obtained is combined with the white precipitate obtained above after filtration. The combined solids are dissolved in benzene (300 mL)
and evaporated. This step is repeated three times to remove traces of water to afford 46.31–47.87 g
yield) of 1
. The purity can be increased by crystallization in ethyl acetate
Dichloromethane (ACS grade) was purchased from Fisher Scientific
and was used as received.
Diethyl ether (ACS grade) was purchased from Fisher Scientific
and was used as received.
Benzaldehyde was purchased from Aldrich Chemical Company, Inc.
and was freshly distilled (70–72 °C, 20 mmHg) prior to use.
The physical properties are as follows: mp 153–155 °C (sealed tube); IR (neat) cm−1
: 725, 748, 756, 888, 1030, 1086, 1109, 1124, 1148, 1191, 1289, 1301, 1312, 1436, 1459, 1597, 2954, 3056, 3205; 31
P NMR (202 MHz, DMSO) δ: 24.98. Due to the very low solubility of the compound in DMSO, clean NMR spectral data are difficult to obtain because minor impurities are much more soluble than the compound of interest.
Granular potassium carbonate was purchased from Aldrich Chemical Company, Inc.
and was ground to a powder using a mortar and pestle then dried under vacuum (100 °C, 1 mmHg).
Anhydrous acetonitrile was obtained by filtration through a drying column on a GlassContour system (Irvine, CA).
The purity is greater than 97% according to the 31
P and 1
H NMR spectra and the only observed impurities are benzaldehyde
. These impurities can be removed on a short pad of silica
gel (EtOAc 100%
). The physical properties of the purified material are as follows: mp 144–146 °C; Rf
0.47 (EtOAc); MS (ESI+) m/z
307.1 (20%), 306.1 (M+
+H, 100%), 233.1 (37%), 219.1 (22%), 201.2 (14%); Anal. calcd for C19
NOP: C, 74.74; H, 5.28; N, 4.59. found: C, 74.45; H, 5.27; N, 4.71; IR (KBr) cm−1
: 704, 729, 752, 832, 848, 926, 998, 1074, 1110, 1127, 1199, 1311, 1368, 1443, 1577, 1597, 1626, 1663, 1698, 2881, 3024, 3056; 1
H NMR pdf
(400 MHz, CDCl3
) δ: 7.39–7.56 (m, 9 H), 7.90–8.02 (m, 6 H), 9.32 (d, J
= 32.2 Hz, 1 H); 13
C NMR (100 MHz, CHCl3
) δ: 128.3 (d, JC-P
= 12.5 Hz), 128.8, 130.0, 131.4 (d, JC-P
= 9.2 Hz), 131.7 (d, JC-P
= 3.6 Hz), 132.8 (d, JC-P
= 127.5 Hz), 133.5, 135.6 (d, JC-P
= 24.2 Hz), 173.5 (dd, JC-P
= 7.7, 3.0 Hz); 31
P NMR (162 MHz, CDCl3
) δ: 24.78.
Cu(OTf)2 was purchased from Strem Chemicals, Inc.
It was stored under argon
atmosphere in a glove-box and was used without prior purification.
was prepared according to the preceeding procedure and was stored under argon
in a glove box.
Anhydrous toluene was obtained by filtration through a drying column on a GlassContour system (Irvine, CA)
is a moisture sensitive and pyrophoric liquid and must be manipulated in an inert atmosphere. Neat diethylzinc was purchased from Aldrich Chemical Co. Inc.
and was used without prior purification.
A PFA coated thermocouple probe, Type K (Omega Engineering, Inc.)
was inserted through the septum after the addition of diethylzinc
to monitor the internal temperature of the reaction solution.
Approximately 35 min are needed to reach that temperature. A Neslab, model CC-65II, cryostat was used to maintain the reaction mixture at 0 °C.
The mixture was dissolved in a minimum amount of dichloromethane
and then was charged onto a column (diameter = 2 cm, height = 15 cm) of 200 g of UltraPure silica
gel (40–63 (m) purchased from Silicycle. The column was eluted with EtOAc and 8-mL fractions were collected. Fractions 15-33 were combined and concentrated by rotary evaporation (30 °C, 50 mmHg). The desired product can be visualized on TLC with a UV lamp or by spraying with a phosphomolybdic acid solution. The Rf
value of the title compound in EtOAc is 0.37.
The physical properties are as follows: mp 127–129 °C; MS (ESI+) m/z
: 337.2 (M+
+H, 21%), 336.1 (M+
, 100%), 233.2 (17%), 219.2 (18%), 218.1 (28%), 201.2 (9%). Anal. calcd. for C21
NOP: C, 75.21; H, 6.61; N, 4.18; found: C, 74.90; H, 6.55; N, 4.35; IR (KBr) cm−1
: 722, 752, 904, 933, 1057, 1090, 1109, 1122, 1182, 1198, 1438, 1460, 2873, 2926, 2963, 3055, 3135; 1
H NMR pdf
(500 MHz, CDCl3
) δ: 0.78 (t, J
= 7.5 Hz, 3H), 1.78–1.88 (m, 1 H), 1.96–2.06 (m, 1 H, exchanges with D2
O), 3.27 (br, 1 H), 4.09 (pent, J
= 8.4 Hz, 1 H), 7.14–7.16 (m, 2 H), 7.21–7.34 (m, 5 H), 7.39–7.50 (m, 4H), 7.75 (ddt, J
= 12.0, 6.9, 1.5 Hz, 2 H), 7.86 (ddt, J
= 12.0, 7.1, 1.3 Hz, 2 H); 13
C NMR (126 MHz, CHCl3
) δ: 10.5, 32.5 (d, JC-P
= 3.9 Hz), 57.1, 126.5, 127.1, 128.3 (d, JC-P
= 12.9 Hz), 128.4, 128.4 (d, JC-P
= 12.9 Hz), 131.7 (d, JC-P
= 2.7 Hz), 131.8 (d, JC-P
= 9.2 Hz), 131.8 (d, JC-P
= 2.8 Hz), 131.9 (d, JC-P
= 131.0 Hz), 132.6 (d, JC-P
= 10.2 Hz), 133.2 (d, JC-P
= 128.0 Hz), 143.5 (d, JC-P
= 5.5 Hz); 31
P NMR (202 MHz, CDCl3
) δ: 22.74; [α]D20 −41.6 (c = 2.14, MeOH)
. The enantiomeric excess of the product is determined by HPLC analysis at 254 nm [Chiralpak, AD, 85:15 hexanes: i-PrOH, 1 mL
(minor) = 10.2 min, (S
(major) = 13.4 min)].
Methanol (ACS grade) was purchased from Fisher Scientific
and was used as received.
The reaction was followed by 31
P NMR spectroscopic analysis. The rate of disappearance of the signal at 23.2 ppm is proportional to the rate of formation of the desired product. The new signals at 34.3 ppm and at 36.6 ppm correspond, respectively, to diphenylphosphinic acid
and methyl diphenylphosphinate
Aqueous concentrated HCl (ACS grade) was purchased from Fisher Scientific
and was used as received.
An ColorpHast indicator strip purchased from EM Science, Inc. was used to measure the pH.
The physical properties are as follows: mp 231–234 °C; MS (EI) m/z
: 135.1, (4%), 106.1 (100%), 79.1 (18%), 74.1 (75%), 59.0, (100%). Anal. calcd. for C9
ClN: C, 62.97; H, 8.22; N, 8.16; found: C, 62.71; H, 8.33; N, 8.18; IR (KBr) cm−1
: 754, 764, 1386, 1394, 1458, 1509, 1600, 2536, 2618, 2685, 2914, 2963, 3035; 1
H NMR pdf
(400 MHz, MeOD) δ: 0.88 (t, J
= 7.3 Hz, 3H), 1.90–2.10 (m, 2 H), 4.15 (dd, J
= 9.5, 5.8 Hz, 1 H), 7.39–7.49 (m, 5 H); 13
C NMR (100 MHz, MeOD) δ: 10.5, 28.7, 58.3, 128.4, 130.3, 130.3, 138.1; [α]D20+16.2 (c = 1.03, MeOH)
The enantiomeric excess of the product was determined on the trifluoroacetyl derivative of the amine by GC analysis with an FID detector (Astec Chiraldex GT-A (30 m × 0.32 mm) 10 psi, 90 °C isothermal): (R
(minor) = 19.59 min, (S
(major) = 20.53 min). To prepare the trifluoroacetamide derivative, 1 mL of 2 M aqueous NaOH
solution was added to 10 mg of the amine hydrochloride
salt in a 5 mL conical vial
. The aqueous layer was extracted with 1 mL of dichloromethane
. The organic layer was dried over Na2SO4 (0.5 g)
, and was decanted into a 5-mL round-bottomed flask
. An egg-shaped magnetic stir bar
and 250 µL of trifluoroacetic anhydride
were added and the mixture was stirred at room temperature under argon
for 5 min. The solvent and excess reagents were removed by rotary evaporation (80 mmHg, 25 °C, 5 min; then 5 mmHg, 25 °C, 10 min). The solid residue was dissolved in 1 mL of dichloromethane
and the liquid was filtered through a syringe filter for GC analysis. For the enantioenriched compounds, the sample was concentrated to ca. 0.1 mL to observe the minor isomer.
The submitters were able to determine the enantiomeric excess of the free amine directly by GC analysis with an FID detector [Beta DexTM
120; 30 °C to 85 °C in 11 min and isothermal thereafter: (R
(minor) = 43.0 min, (S
(major) = 43.6 min)].
All hazardous materials should be handled and disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
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