Org. Synth. 2005, 82, 147
DOI: 10.15227/orgsyn.082.0147
PREPARATION OF [1-(METHOXYMETHYLCARBAMOYL)ETHYL] PHOSPHONIC ACID BIS-(2,2,2-TRIFLUOROETHYL) ESTER: A USEFUL INTERMEDIATE IN THE SYNTHESIS OF Z-UNSATURATED N-METHOXY-N-METHYLAMIDES
Submitted by Amos B. Smith, III, Jason J. Beiger, Akin H. Davulcu, and Jason M. Cox
1.
Checked by Mark Lautens and Catherine Taillier.
1. Procedure
A. Ethylphosphonic acid bis-(2,2,2-trifluoroethyl) ester (2).
2 A flame-dried
2-L three-necked round-bottom flask equipped with a
Teflon-coated magnetic stir bar,
thermometer, rubber septum and argon inlet (Note 1) is charged with
24.1 mL (336 mmol, 2.01 eq.) of 2,2,2-trifluoroethanol (Notes
2,
3) and
500 mL of anhydrous THF (Note 4) under an
argon atmosphere, and cooled to an internal temperature of 0 °C with an ice-NaCl bath for 10 min. The above flask is then charged dropwise with
51.3 mL (369 mmol, 2.20 eq.) of triethylamine (Note 5) over 10 min., and stirred at 0 °C for 15 min. A separate
flame-dried 250-mL one-necked round-bottom flask equipped with a rubber septum and
argon inlet is charged with
17.9 mL (167 mmol, 1.00 eq.) of ethylphosphonic dichloride 1
(Note 2) and
65 mL of THF under an
argon atmosphere. The mixture is stirred, and transferred dropwise
via cannula (Notes
3,
6) into the
trifluoroethanol/
triethylamine solution over 15 min while maintaining the internal temperature below 12 °C. The 250-mL flask is then rinsed with
THF (2 × 10 mL), and the THF washes transferred by cannula to the larger flask over a five-minute period. The resulting white slurry is warmed to room temperature over 15 min., stirred at room temperature for 2.25 h, filtered through a sand-covered frit
(Note 7), and concentrated by rotary evaporation (35 °C, 20 mmHg) to afford
43 g of a cloudy, nearly colorless liquid. The latter is transferred to a
100-mL one-necked round-bottom flask equipped with a
Teflon-coated magnetic stir bar and a short path distillation head fitted with a distribution adapter and three 50-mL pear-shaped receiving flasks. After collecting a forerun (ca. 1 mL), the product is distilled under an aspirator vacuum (
bp = 92–95 °C at 25 mmHg) to yield
40.85 g (
89%) of
ethylphosphonic acid bis-(2,2,2-trifluoroethyl) ester (2) as a clear colorless liquid
(Note 8).
B. N-Methoxy-N-methylcarbamoyl chloride (4).
3 A flame-dried 500-mL three-necked round-bottom flask equipped with a Teflon-coated magnetic stir bar, thermometer, rubber septum and argon inlet is charged with
10.1 g (34.1 mmol, 0.400 eq.) of triphosgene (Note 2) and
57 mL of anhydrous dichloromethane (Note 4) under an
argon atmosphere, and cooled to an internal temperature of −78 °C with a dry ice-
acetone bath for 20 min. The suspension is charged with
8.33 g (85.4 mmol, 1.00 eq.) of N,O-dimethylhydroxylamine hydrochloride 3
(Note 2) in three portions by briefly removing the septum and using a powder funnel with 5 min. elapsing between each portion while maintaining the internal temperature below −70 °C. The suspension is recooled to −78 °C and stirred for 30 min. A
separate flame-dried, 100-mL round-bottomed flask equipped with a
rubber septum and argon inlet is charged with
13.7 mL (171 mmol, 2.00 eq.) of pyridine (Note 5) and
28 mL of dichloromethane under an
argon atmosphere. The mixture is stirred and transferred dropwise
via cannula to the above hydroxylamine/
triphosgene suspension over 1.5 h while maintaining the internal temperature below −72 °C
(Note 6). The 100-mL flask is rinsed with
dichloromethane (2 × 5 mL), and the
dichloromethane washes transferred by cannula to the larger flask over 5 min. The resulting yellow-orange slurry is slowly warmed to room temperature over 4 h, stirred at room temperature for 12.5 h, quenched with 100 mL of distilled water, and transferred to a
500-mL separatory funnel. The layers are separated, and the aqueous layer extracted with
dichloromethane (3 × 50 mL). The combined organic phases are sequentially washed
(Note 5) with aqueous
0.5 M HCl (2 × 100 mL), saturated aqueous
NaHCO3 (1 × 75 mL), and
brine (1 × 75 mL), dried
(Na2SO4), filtered, and concentrated by rotary evaporation (35 °C, 20 mmHg) to afford
11.3 g of a yellow liquid. The yellow liquid is transferred to a
50-mL one-necked round-bottom flask equipped with a Teflon-coated magnetic stir bar and a short path distillation head fitted with a distribution adapter and
three 25-mL pear-shaped receiving flasks. After collecting a forerun (
ca. 0.5 mL), the product is distilled under vacuum aspirator (
bp = 67–69 °C at 25 mmHg) to afford
8.87-9.18 g (
84-87%) of
N-methoxy- N-methylcarbamoyl chloride 4 as a clear colorless liquid
(Note 9).
C. [1-(Methoxymethylcarbamoyl)ethyl] phosphonic acid bis-(2,2,2-trifluoroethyl) ester (
5).
4 A
flame-dried 1-L three-necked round-bottom flask equipped with a
Teflon-coated magnetic stir bar,
thermometer,
rubber septum and argon inlet is charged with
51.0 mL (128 mmol, 2.41 eq.) of a 2.5 M solution of n-butyllithium in hexanes
(Note 2) and
40 mL of THF under an argon atmosphere, and cooled to an internal temperature of −20 ± 3 °C with a dry ice-
isopropanol-water bath for 20 min. In a separate
flame-dried 100-mL one-necked round-bottom flask equipped with a
rubber septum and argon inlet is charged with
29.2 mL (139 mmol, 2.64 eq.) of 1,1,1,3,3,3-hexamethyldisilazane (HMDS)
(Note 2) and
40 mL of THF under an argon atmosphere. The mixture is stirred and transferred dropwise
via cannula to the above
n-butyllithium solution over 20 min while maintaining the internal temperature below −15 °C
(Note 6). The 100-mL flask is then rinsed with
THF (2 10 mL), and the THF washes cannulated to the larger flask over 5 min. The resulting clear solution is stirred at −20 ± 3 °C for 20 min., and cooled to an internal temperature of −75 °C with a dry ice-
acetone bath. A separate
flame-dried 100-mL one-necked round-bottomed flask equipped with a
rubber septum and argon inlet is then charged with
14.5 g (52.9 mmol, 1.00 eq.) of ethylphosphonic acid bis-(2,2,2-trifluoroethyl) ester 2,
2 9.00 g (72.9 mmol, 1.38 eq.) of N-methoxy-N-methylcarbamoyl chloride 4,
3 and
50 mL of THF, and transferred dropwise
via cannula to the above lithium HMDS solution over 30 min. while maintaining the internal temperature below −68 °C
(Note 6). The smaller flask is rinsed with
THF (2 × 10 mL), and the THF washes transferred by cannula to the larger flask over 5 min. The resulting pale yellow solution is recooled to −75 °C and stirred for 2.5 h
(Note 10), then slowly acidified over 5 min. with
130 mL of a 1.0 M solution of HCl, and gradually warmed to an internal temperature of 0 °C over 30 min. The solution is diluted with
100 mL of distilled water, and transferred to a
1-L separatory funnel. The flask is rinsed with
diethyl ether (3 × 50 mL), transferred to the funnel, shaken, the layers separated, and the aqueous layer extracted with
dichloromethane (4 × 100 mL) (Note 11). The combined organic phases are dried
(MgSO4), filtered, and concentrated by rotary evaporation (35 °C, 20 mmHg) to afford
19 g of a yellow oil
(Note 12). The yellow oil is loaded onto a 80-mm diameter column, wet-packed (4:1 hexanes:
ethyl acetate) with 450 grams (25 cm) of
silica gel
(Note 13), and sequentially eluted with a gradient of hexanes and
ethyl acetate (2 L of 2:1, 2 L of 1:1, 1 L of 1:2). The desired product is collected in fractions of 75-mL volume, concentrated by rotary evaporation (35 °C, 20 mmHg), and dried under vacuum (25 °C, 0.01 mmHg) until a constant mass is obtained. The above described procedure affords
15.6 - 16.8 g (
82–88%) of
[1-(methoxymethylcarbamoyl)ethyl] phosphonic acid bis-(2,2,2-trifluoroethyl) ester 5 as a clear pale yellow oil
(Note 14).
2. Notes
1.
All flasks were flame-dried and maintained under an
argon atmosphere during the course of the reactions. The argon was dried and purified by passing through Drierite
® and then an Oxiclear
™ disposable gas purifier, which may be purchased from Aldrich Chemical Co., Inc. A gas manifold was then used to distribute
argon to each of the attached flasks. An
argon inlet was affixed to a flask by inserting its needle through that flask's rubber septum while maintaining slightly positive pressure.
2.
2,2,2-Trifluoroethanol (≥ 99%), ethylphosphonic dichloride (98%), triphosgene (98%), N,O-dimethylhydroxylamine hydrochloride (98%), 1,1,1,3,3,3-hexamethyldisilazane (99.9%) and the 2.5 M solution of n-butyllithium in hexanes were purchased from Aldrich Chemical Co., Inc. and used as received.
3.
Liquids were added to flasks from plastic disposable syringes through stainless steel needles. Liquids were transferred between flasks
via stainless steel cannulas. All needles and cannulas were oven-dried for at least one hour and cooled to room temperature in a dessicator prior to use.
4.
HPLC grade dichloromethane (99.9%) and
tetrahydrofuran (THF) (99.9%) were purchased from Fisher Scientific. Dichloromethane and THF were dried by purging with
argon over activated molecular sieves and were stored under
argon at room temperature. The checkers used THF distilled from Na/
benzophenone ketyl and
dichloromethane purified with a MBRAUN® Solvent Purification System.
5.
Triethylamine (99%), pyridine (99.9%), dichloromethane, hexanes, ethyl acetate, sodium chloride, sodium bicarbonate, anhydrous magnesium sulfate, anhydrous sodium sulfate, and concentrated hydrochloric acid were purchased from Fisher Scientific and used as received.
Triethylamine and
pyridine were used by the checkers after distillation over KOH.
6.
Alternatively, a
flame-dried 100-mL additional funnel may be used to regulate the rate at which the reaction flask is charged with solution.
7.
Alternatively, filtration of the resulting white slurry through a short plug of Celite could be performed to remove the ammonium salts.
8.
Ethylphosphonic acid bis-(2,2,2-trifluoroethyl) ester 2 displays the following spectroscopic properties: IR (film): 2974 (weak), 1463, 1419, 1287, 1255, 1174, 1109, 1079, 1036, 964, 868, 844 cm
−1;
1H NMR
pdf (400 MHz, CDCl
3) δ: 4.30-4.47 (m, 4H), 1.93 (dq,
JPH = 18.7 and
JHH = 7.7 Hz, 2H), 1.22 (dt,
JPH = 21.5 and
JHH = 7.7 Hz, 3H);
13C NMR (100 MHz, CDCl
3) δ: 122.6 (qd,
JCF = 277.6 and
JCP = 7.7 Hz), 61.8 (qd,
JCF = 37.6 and
JCP = 6.1 Hz), 18.9 (d,
JCP = 143.4 Hz), 5.9 (d,
JCP = 7.7 Hz); The checkers have not been able to get an elemental analysis due to volatility of compound
2. However, the submitters reported the following data for
2: Anal. Calcd for C
6H
9F
6O
3P: C, 26.29; H, 3.31. Found: C, 26.20; H, 3.06.
9.
The following characterization data were obtained for
N-methoxy-N-methylcarbamoyl chloride (
4): IR (film): 2982, 2941, 1732 (broad), 1460, 1443, 1406, 1352, 1182, 1082, 995, 868, 669, 653 cm
−1;
1H NMR
pdf (500 MHz, CDCl
3) δ: 3.78 (s, 3H), 3.33 (s, 3H). The checkers have not been able to get an elemental analysis due to volatility of compound
4. However, the submitters reported the following data for
4: Anal. Calcd for C
3H
6ClNO
2: C, 29.17; H, 4.90. Found: C, 29.02; H, 4.89.
10.
The reaction was monitored by thin layer chromatography (TLC) with 0.25-mm E. Merck pre-coated silica gel plates. The plates were eluted with a 1:1 mixture of hexanes and
ethyl acetate. The R
f values of
2,
4, and
5, are 0.55, 0.70, and 0.21, respectively. A
potassium permanganate-based stain that was prepared by dissolving
3 g of KMnO4,
20 g of K2CO3, and
5 mL of 5% aqueous NaOH in 300 mL of distilled water was suitable for visualizing the product on TLC.
11.
If an emulsion occurs during the
dichloromethane extractions, it may be broken with the addition of approximately
15 mL of brine. Checkers found that filtration of the biphasic mixture through a short plug of Celite was necessary to break the emulsion.
12.
The crude mixture may be distilled under vacuum through a short path apparatus (bp = 105–107 °C at 0.01 mmHg) to yield phosphonate
5 as a slightly pale yellow oil. Purification by this method, however, resulted in a significantly lower yield (
40–50%) due to thermal decomposition of
5.
13.
Silica gel may be purchased from Silicycle Chemical Division. The silica gel used by the submitters had the following specifications: pH: 6.5–7.0, particle size: 40–63 µm (230–400 mesh), spec. surface area: 500 m
2/g, pore diameter: 60 Å.
14.
Phosphonate
5 exhibits the following spectroscopic properties: IR (film): 2976, 2949, 1651, 1455, 1418, 1393, 1259, 1173, 1072, 987, 962, 845 cm
−1;
1H NMR
pdf (400 MHz, CDCl
3) δ: 4.43-4.57 (m, 2H), 4.35-4.47 (m, 2H), 3.78 (s, 3H), 3.77 (m, 1H), 3.28 (s, 3H), 1.50 (dd,
J = 19.8 and
J = 7.3 Hz, 3H);
13C NMR (100 MHz, CDCl
3) δ: 169.3, 122.6 (qdd,
JCF = 277.6,
JCP = 22.6 and
JCP = 8.8 Hz), 63.1 (qd,
JCP = 37.6 and
JCP = 5.0 Hz), 61.8 (qd,
JCP = 38.3 and
JCP = 6.1 Hz), 61.7, 35.7 (d,
JCP = 142.6 Hz), 32.0, 12.4 (d,
JCP = 7.7 Hz); MS-ESI
m/
z (relative intensity): 284 (M+Na
+, 100%), 362 (M+H
+, 81%), 319 (27%), 301 (22%), 273 (25%), 245 (8%); High resolution mass spectrum (ES + )
m/z 384.0393 [(M + Na)
+; calcd for C
9H
14F
6NNaO
5P: 384.0411]. Anal. Calcd for C
9H
14F
6NO
5P: C, 29.93; H, 3.91; N, 3.88. Found: C, 29.97; H, 3.93; N, 3.92.
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 methods described herein illustrate a practical and convenient three-step synthesis of bis(2,2,2-trifluoroethyl)phosphonates in good overall yield (> 66%). This class of phosphonates, bearing an
N-methoxy-
N-methylamide functionality, is synthetically useful for the construction of
Z-unsaturated
N-methoxy-
N-methylamides.
4 It is well established that the Weinreb amide functionality may then be converted to aldehydes or ketones in good yields.
5The formation of
bis(2,2,2-trifluoroethyl)phosphonate 5 was previously reported by Deslongchamps et al.
4 following procedures developed by Tius and Busch-Petersen that employed KF/alumina to construct α-heterosubstituted Weinreb amides.
6 They discovered that
tris(2,2,2-trifluoroethyl) phosphite reacts with bromides bearing the
N-methoxy-
N-methylamide moiety (
6,
7) to furnish the respective phosphonates
8 and
5 in modest yield (eq. 1).
The procedure described herein proceeds in higher yield and circumvents the difficulty of handling and preparing the KF/alumina reagent. For example, although reactivity of the halide increases as the ratio of fluoride salt versus alumina is increased, the reagents became very hygroscopic and difficult to handle.
7 Additionally, Ando et al. discovered that a trace amount of water was essential for promoting the reaction, and thorough drying of the KF/alumina reagent led to a significant reduction in reactivity.
6,8 On the other hand, too much residual water was found to hydrolyze the chlorine analog of Weinreb amide
6.
6 Tius and Busch-Petersen also reported that continuous sonication of the reaction mixture was necessary to enhance the reactivity of the KF/alumina reagent.
6,9
Deslongchamps et al. subsequently demonstrated the utility of phosphonates
5 and
8 in the stereoselective formation of
Z-unsaturated alkenes using the modified Still conditions.
4,10 Bis(2,2,2-trifluoroethyl)phosphonates
8 and
5 react with aldehydes
9–
12 to furnish the respective unsaturated
N-methoxy-
N-methylamides
13–
17 in 81–89% yield, with only the
Z isomer detectable by
1H-NMR (eq. 2).
4Table 1 illustrates the several aldehydes (
9–
12) that Deslongchamps et al. employed to demonstrate the versatility of bis(2,2,2-trifluoroethyl)phosphonates
5 and
8 in the stereoselective synthesis of
Z-unsaturated
N-methoxy-
N-methylamides
13–
17.
4
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
n-Butyllithium:
Lithium, butyl- (8,9); (109-72-8)
Ethanamine, N,N-diethyl- (9); (121-44-8)
Ethanol, 2,2,2-trifluoro- (6,8,9); (75-89-8)
Ethylphosphonic acid bis-(2,2,2-trifluoroethyl) ester: 650-16-8
Phosphonic acid, ethyl-, bis(2,2,2-trifluoroethyl) ester (6, 8, 9); (650-16-8)
1,1,1,3,3,3-Hexamethyldisilazane:
Silanamine, 1,1,1-trimethyl-N-(trimethylsilyl)- (9); (999-97-3)
Methanamine, N-methoxy-, hydrochloride (9); (6638-79-5)
Methanol, trichloro-, carbonate (2:1) (9); (32315-10-9)
N-Methoxy-N-methylcarbamoyl chloride:
Carbamic chloride, methoxymethyl- (9); (30289-28-2)
[1-(Methoxymethylcarbamoyl)ethyl]phosphonic acid bis-(2,2,2-trifluoroethyl) ester:
Phosphonic acid, [2-(methoxymethylamino)-1-methyl-2-oxoethyl]-, bis(2,2,2-trifluoroethyl) ester (9); (448219-33-8)
Phosphonic dichloride, ethyl- (6,7,8,9); (1066-50-8)
Pyridine (6,7,8,9); (110-86-1)
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