Organic Syntheses, CV 9, 436
Submitted by B. C. Hamper
1
Checked by T. Harrison and Larry E. Overman.
1. Procedure
A.
Ethyl 4,4,4-trifluoro-2-(triphenylphosphoranylidene)acetoacetate. A
2-L, four-necked, round-bottomed flask is equipped with a
nitrogen line attached to a bubbler, a
250-mL pressure-equalizing funnel, an overhead stirrer and a thermometer. The flask is charged with
215 g (0.5 mol) of (carbethoxymethyl)triphenylphosphonium bromide and
1.1 L of anhydrous tetrahydrofuran (THF) (Note
1) and (Note
2). The stirred suspension is cooled in an
ice water bath and treated with
150 mL (1.1 mol) of triethylamine (Note
3) added dropwise over 5 min. After the mixture is stirred for an additional 30 min at 5°C, it is treated dropwise with
78 mL (116 g, 0.55 mol) of trifluoroacetic anhydride (Note
4) in such a manner that the reaction temperature is maintained between 5–10°C, which results in a total addition time of approximately 1 hr. The mixture is allowed to stir for 2 hr and subsequently filtered, the precipitate is washed three times with cold
THF and the filtrate is concentrated under reduced pressure to afford a yellow oily residue. Trituration of the residue with 600 mL of water affords a crystalline product which is collected, washed three times with 100 mL of water, and dried by suction to afford
208 g of a yellowish colored solid (Note
5). The solid is dissolved in
900 mL of hot methanol; the solution is filtered, treated with 500 mL of water, and placed in a refrigerator overnight. The crystalline product is collected, washed three times with 100 mL of cold water and dried under reduced pressure to afford
200–208 g (
89–93%) of
ethyl 4,4,4-trifluoro-2-(triphenylphosphoranylidene)acetoacetate as a very pale-yellow, crystalline solid (Note
6).
B.
Ethyl 4,4,4-trifluorotetrolate. A
1-L, three-necked, round-bottomed flask is equipped with an
efficient magnetic stirrer, a
heating mantle, a
thermocouple (Note
7) and a large bore gas exit tube (
f.htmigure 1, (Note
8)). To this flask are added
200 g (0.45 mol) of ethyl 4,4,4-trifluoro-2-(triphenylphosphoranylidene)acetoacetate and
40 g of potassium carbonate (Note
9). The gas exit tube is connected to a
Dewar condenser, modified with a side arm connection, which has a round-bottomed flask for collection of the product in a
dry ice-acetone bath. A second
trap is placed between the reaction setup and the
vacuum pump, all the traps are cooled with dry ice-acetone, and the system is evacuated to 1–2 mm. The reaction flask is carefully heated to 150°C (Note
10) at which point the phosphorane melts and the
acetylene evolution begins. The molten phosphorane is stirred and heated from 160°C to 220°C over a period of 5 hr. Heating is carefully increased during the reaction in order to control the rate of distillation of the acetylenic product. From the round-bottomed flask in the cold trap is obtained
65–67 g (
87–89%) of a clear, slightly yellow, liquid. The thermolysis product is dried with
magnesium sulfate and filtered through Celite. Distillation at atmospheric pressure through a short-path distillation apparatus affords about 1.0 g of forerun and
59–61 g (
79–82%) of
ethyl 4,4,4-trifluorotetrolate as an analytically pure, colorless liquid, bp
760 97–100°C (Note
11).
Figure 1
2. Notes
2. We have found it more convenient to prepare
(carbethoxymethyl)triphenylphosphonium bromide in situ in the same reaction vessel from
triphenylphosphine and
ethyl bromoacetate. This effectively provides a one-pot preparation for the α-acylmethylenephosphorane from
triphenylphosphine and allows facile incorporation of various esters, by employing different bromoacetate esters, in the acetylenic product. The yield and purity of the resultant phosphorane is unaffected by the following one-pot procedure.
A 2-L, four-necked, round-bottomed flask is equipped with a nitrogen line attached to a bubbler, a 250-mL pressure-equalizing funnel, an overhead stirrer and a thermometer. The flask is charged with
132 g of triphenylphosphine (0.503 mol) and
500 mL of anhydrous tetrahydrofuran and cooled in an
ice water bath to 5°C. The stirred solution is treated dropwise with
56 mL of ethyl bromoacetate (84 g, 0.503 mol) added at such a rate that the temperature is maintained between 8°C and 10°C. The total addition time is about 15 min. After the mixture is stirred overnight, it is diluted with an additional
600 mL of anhydrous tetrahydrofuran and the precipitate is washed from the sides of the flask. The resultant suspension of
(carbethoxymethyl)triphenylphosphonium bromide is cooled in an ice-water bath and used directly in the same pot to prepare α-acylmethylenephosphoranes as detailed in section A.
3.
Triethylamine was supplied by Eastman Kodak Company and Fisher Scientific Company.
5. The yellow crystalline solid is analytically pure (>95% by NMR and HPLC analysis), mp
124–127°C. We have found that the yield of the acetylenes can be adversely affected by small amounts of impurities in the α-acylmethylenephosphoranes and prefer to recrystallize the phosphoranes prior to thermolysis. The yield from the recrystallization step is greater than
95%.
6. The phosphorane softens above 120°C and melts between
125–130°C (lit.
2,3 mp
125–127°C). Spectral properties of the phosphorane are as follows:
1H NMR (500 MHz, CDCl
3) δ: 0.87 (t, 3 H, J = 7.2), 3.81 (q, 2 H, J = 7.2), 7.49 (dt, 6 H, J = 7.9, 3.3), 7.57 (m, 3 H), 7.67 (dd, 6 H, J = 12.9, 7.9);
13C NMR (125 MHz, CDCl
3) δ: 13.5, 59.8, 70.1 (d,
1J
CP = 110), 117.9 (dd,
1J
CF = 288,
3J
CP = 14.6), 123.7 (d,
1J
CP = 93.3), 128.8 (d,
2J
CP = 13.0), 132.2 (d,
4J
CP = 3.0), 133.2 (d,
3J
CP = 10.0), 165.6 (d,
2J
CP = 13.0), 174.4 (dd,
2J
CF = 34.0,
2J
CP = 5.8);
31P NMR (202 MHz, CDCl
3) δ: 19.8. Anal. Calcd for C
24H
20O
3F
3P: C, 64.87; H, 4.54. Found: C, 64.96; H, 4.60.
7. A
stainless steel-covered thermocouple is preferred since it is less likely to break than a
mercury thermometer. As the phosphorane begins to melt, large chunks of solid remain as the mixture is initially stirred, and these can lodge between a thermometer and the walls of the flask. The thermocouple has the added advantage that the steel rod can be used to help break up the melting phosphorane, taking care to avoid breaking the flask.
8. The large bore gas exit tube (
f.htmigure 1) used between the reaction flask and the Dewar condenser is a glass tee equipped with the appropriate 24/40 ground glass joints. Alternatively, the connection can be made using large bore, thick wall Tygon or vacuum tubing.
9. In the absence of
potassium carbonate, the thermolysis product is slightly acidic and the pH of a water wash of freshly collected product is about 1.
10.
CAUTION! Care must be taken not to heat the phosphorane too rapidly, particularly before the solid has melted. The temperature of the molten material is not at equilibrium until the mixture has completely melted. If it is heated too rapidly, it is difficult to control the rate of acetylene production. It is best to heat slowly until a stirred, molten material is obtained and to continue heating at such a rate as to control acetylene formation. We have obtained excellent results applying initially 30 volts to a 380-watt, 115-volt, 1-L heating mantle obtained from Glas-Col Apparatus Company. Alternatively, more even and controlled heating can be obtained by using a
large oil bath.
11. Previous literature reports
3 bp
96–98°C. Spectral properties of the
acetylene are as follows:
1H NMR (500 MHz, CDCl
3) δ: 1.34 (t, 3 H, J = 7.1), 4.32 (q, 2 H, J = 7.1);
13C NMR (125 MHz, CDCl
3) δ: 13.8, 63.5, 69.9 (q,
2J
CF = 54.0), 75.5 (q,
3J
CF = 6.0), 113.4 (q,
1J
CF = 259), 150.7; IR (neat) cm
−1: 2987, 2275 (w); 1731. Anal. Calcd for C
6H
5O
2F
3: C, 43.49; H, 3.03. Found: C, 43.14; H, 3.07.
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Thermolysis of α-acylmethylenephosphoranes is the most convenient method for preparation of acetylenes with perfluoroalkyl substituents.
3,4 Many of these acetylenes, particularly the trifluoromethyl analogs, are particularly volatile and thermolysis allows preparation and collection of material which is free of solvents or impurities of similar boiling point. In addition, the acetylenes are prepared from readily available starting materials with overall conversions for the two steps of greater than 75% in many cases. Attempts to prepare
trifluorotetrolic acid by carbonylation of the
lithium acetylenide of
3,3,3-trifluoropropyne have been unsuccessful.
5 However, the treatment of lithium acetylenides with chloroformates affords perfluoroalkyl-substituted propiolates (the perfluoroalkyl group is a C
4 chain length or longer) in 38–43% yield along with an unusual by-product.
6 Benzyl trifluorotetrolate, which was employed in the synthesis of a trifluoromethyl analog of
geraniol, has been prepared from
ethyl trifluoroacetoacetate via a pyrazolone in an overall yield of 55%.
7 A number of (difluoroalkyl)propiolates, employed in Diels-Alder cycloaddition reactions, have been prepared by treatment of the corresponding ketones with
diethylaminosulfur trifluoride (DAST).
8 The corresponding (difluoroalkyl)propiolic acids have also been prepared by carbonylation of the
magnesium bromoacetylenide.
9
The utility of the phosphorane route to electron-deficient acetylenes depends on the facile synthesis of the α-acylmethylenephosphorane intermediates. Previously they had been prepared by a two-step procedure from the available phosphonium salts, requiring isolation of the Wittig reagent [e.g.,
(ethoxycarbonylmethylene)triphenylphosphorane] intermediate.
3,4 Acylation of the Wittig reagent affords, via transylidation,
10 a 1:1 mixture of components which must be separated prior to thermolysis. In addition, at least half of the Wittig reagent is lost by conversion to the starting phosphonium salt. The addition of a suitable base, such as
triethylamine, to the reaction mixture avoids the undesired transylidation reaction and affords complete conversion to the desired α-acylmethylenephosphorane. For acyl halides which have an acidic hydrogen α to the carbonyl group, treatment with base can give rise to ketenes which readily react with Wittig reagents to afford allenes.
11 This route, using
triethylamine as a base, has been explored to prepare allenes that are either substituted or unsubstituted in the α-position.
For acyl halides or anhydrides which do not afford ketenes in the presence of base (such as perfluoroacyl halides), however, the α-acylmethylenephosphoranes can be prepared directly in one step from the phosphonium salts by using two equivalents of base by the present procedure (Table I).
2 Both
tetrahydrofuran and
methylene chloride have been used as solvents; in the case of the title compound,
tetrahydrofuran provides the best results. Good yields of the phosphoranes are generally obtained when R
1 is an electron-withdrawing group such as ester or nitrile. The yields of phosphoranes obtained for the thiomethyl or phenyl cases can be improved by using
1,4-diazabicyclo[2.2.2]octane (DABCO) rather than
triethylamine as the base.
TABLE I
PREPARATION OF (α-ACYLMETHYLENE)PHOSPHORANES FROM α-SUBSTITUTED METHYLPHOSPHONIUM SALTS2
|
|
R1 |
R2 |
Solvent |
Base |
Yield (%) |
|
CO2Et |
CF3 |
CH2Cl2 |
Et3N |
54 |
CO2Me |
CF3 |
THF |
Et3N |
99 |
CO2Et |
CF2CF3 |
THF |
Et3N |
69 |
CN |
CF3 |
THF |
Et3N |
75 |
SCH3 |
CF3 |
THF |
Et3N |
49 |
Ph |
CF3 |
CH2Cl2 |
Et3N |
24 |
Ph |
CF3 |
CH2Cl2 |
DABCO |
57 |
|
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
potassium carbonate (584-08-7)
acetylene (74-86-2)
methanol (67-56-1)
methylene chloride (75-09-2)
magnesium sulfate (7487-88-9)
Ethyl bromoacetate (105-36-2)
Tetrahydrofuran,
THF (109-99-9)
geraniol (106-24-1)
triethylamine (121-44-8)
triphenylphosphine (603-35-0)
trifluoroacetic anhydride (407-25-0)
1,4-diazabicyclo[2.2.2]octane (280-57-9)
Diethylaminosulfur trifluoride (38078-09-0)
(ethoxycarbonylmethylene)triphenylphosphorane (1099-45-2)
Ethyl 4,4,4-trifluorotetrolate,
2-Butynoic acid, 4,4,4-trifluoro-, ethyl ester (79424-03-6)
Ethyl 4,4,4-trifluoro-2-(triphenylphosphoranylidene)acetoacetate (83961-56-2)
(carbethoxymethyl)triphenylphosphonium bromide (1530-45-6)
trifluorotetrolic acid
lithium acetylenide
3,3,3-trifluoropropyne (661-54-1)
Benzyl trifluorotetrolate
ethyl trifluoroacetoacetate
magnesium bromoacetylenide
METHYLPHOSPHONIUM
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