Org. Synth. 2006, 83, 177
DOI: 10.15227/orgsyn.083.0177
TRIFLUOROMETHYLATION AT THE α-POSITION OF α,β-UNSATURATED KETONES: 4-PHENYL-3-(TRIFLUOROMETHYL)BUTAN-2-ONE
Submitted by Kazuyuki Sato
1, Masaaki Omote, Akira Ando, and Itsumaro Kumadaki.
Checked by Scott E. Denmark and Won-jin Chung.
1. Procedure
CAUTION! Neat diethylzinc may ignite on exposure to air and reacts violently with water. It must be handled and reacted under nitrogen. The reaction solvent must be dried and distilled prior to use and all glassware and syringes must be thoroughly dried.
4-Phenyl-3-trifluoromethyl-2-butanone. A flame-dried, 500-mL, four-necked, round-bottomed flask is equipped with a rubber septum, a dry ice/isopropyl alcohol cooled cold-finger condenser topped with a nitrogen stopcock inlet, a pressure-equalizing dropping funnel topped with a rubber septum, a Teflon-coated thermocouple (Note 1), and a Teflon-coated magnetic stirring bar. The reaction vessel is charged with 4-phenylbut-3-en-2-one (7.310 g, 50 mmol), RhCl(PPh3)3 (925 mg, 1.0 mmol) (Note 2), and 190 mL of tetrahydrofuran (THF) is added under nitrogen (Note 2). The brown solution is cooled in an isopropyl alcohol bath to −30 °C (Note 3). In a graduated tube equipped with a three-way stopcock attached to a nitrogen inlet from a Schlenk line, 7 mL (ca. 86 mmol) of trifluoroiodomethane (CF3I) (Note 4) is condensed at −78 °C by using a dry ice/isopropyl alcohol bath. After the CF3I condenses, the three-way stopcock is closed and the top of the stopcock is fitted with a rubber septum. The condensed CF3I is added to the reaction mixture quickly through a cannula by warming the graduated tube with a water bath. After almost all of CF3I is transferred to the reaction vessel, 10 mL of THF is added to the graduated test-tube through the septum, and the THF is transferred to the reaction vessel through the cannula by briefly evacuating the reaction vessel through a hose to the Schlenk line. The reaction mixture is immersed in an ice-bath, and then diethylzinc in hexane solution (75 mL 1.0 M) (Note 5) is gradually added to the solution through the presser-equalizing dropping funnel over 2 h. During the addition, the temperature of the solution is kept below 5 °C by cooling with an ice bath. The reaction mixture is allowed to warm to room temperature over 30 min after removing the ice-bath, whereupon it is stirred at room temperature for 1 h (Note 6). The progress of the reaction is followed by thin layer chromatographic (TLC) analysis (Note 7), which confirms that the reaction is complete (Note 8). The resulting mixture is carefully poured into a mixture of 10% HCl (150 mL) and ice (about 50 g) in a 1-L Erlenmeyer flask equipped with a Teflon-coated magnetic stirring bar (Note 9). The ice melts in a few minutes, then the mixture is extracted with Et2O (4 × 150 mL). The combined organic layers are washed with brine (100 mL) and then are dried over MgSO4 (about 20 g). The MgSO4 is removed by filtration through a sintered glass-filter, and the solvent is removed under reduced pressure on a rotary evaporator (23 °C, 30 mm Hg). The residue is purified by silica gel (Note 10) column chromatography (190 g, diameter = 50 mm, eluted with hexane/ethyl acetate, 30/1; 1.2 L) to remove small amounts of impurities and most of the black color. The product-containing portions are concentrated under reduced pressure, and are purified by reduced-pressure distillation using short path distillation apparatus (66–68 °C / 3 mmHg) to afford 7.610 g (72 %) of 4-phenyl-3- (trifluoromethyl)butan-2-one as a clear, colorless oil (Notes 10 and 11).
2. Notes
1.
A PFA coated thermocouple probe, Type K (Omega Engineering, Inc.) was inserted through the septum.
2.
4-Phenylbut-3-en-2-one (>99%) and RhCl(PPh3)3 (>99.99%) were purchased from Aldrich Chemical Co. and were used without further purification. The reaction apparatus is shown in Figure 1. The submitters used
argon.
3.
Anhydrous
THF was obtained by filtration through an alumina drying column on a GlassContour system (Irvine, CA).
4.
CF3I was purchased from Aldrich Chemical Co. (99%). Its boiling point is −22.1 °C, and density is about 2.4 g/mL.
CF3I was transferred from the container to the graduated test-tube by using the apparatus shown in Figure 2. The tube was evacuated and cooled below −78 °C in a dry ice/
isopropyl alcohol bath. Then the vacuum line was closed, stopcock
A was opened and the correct amount of CF
3I was collected in the graduated test-tube.
5.
Diethylzinc (1.0 M in
hexane solution) was purchased from Aldrich Chemical Co. It was transferred to the pressure-equalizing addition funnel via cannula by briefly evacuating the reaction flask through the Schlenk line.
Figure 1. Reaction Apparatus for the Synthesis of α-CF3 Ketones
Figure 2. Apparatus for Collecting CF3I
6.
A mild evolution of gas was observed upon addition of
diethylzinc. The composition of the gas was not determined, but it is most likely
trifluoromethyl iodide and/or
ethylene. As the reaction mixture was warmed to room temperature, slight gas evolution was observed, and the color of the solution changed to dark brown.
7.
TLC analysis was performed on Merck silica gel plates with QF-254 indicator and
hexane/
ethyl acetate, 9/1 as eluent. Visualization was accomplished with UV light and KMnO
4 staining solution.
8.
An aliquot of the reaction mixture was removed and quenched with 10% aq. HCl, then Et
2O was added. The organic phase was analyzed by TLC (see
Note 7).
4-Phenylbut-3-en-2-one (R
f = 0.23) almost disappeared after 0.5 h, but
4-phenylbutan-2-one, (R
f = 0.29) which can be generated by quenching the corresponding rhodium enolate was still present. After 1.0 h,
4-phenylbutan-2-one disappeared and only
4-phenyl-3-(trifluoromethyl) butan-2-one (R
f = 0.50) was detected. The submitters used gas chromatography to monitor the reaction progress.
9.
Vigorous evolution of gas was observed upon quenching.
10.
The submitters found that
4-phenyl-3-(trifluoromethyl)butan-2-one is stable at room temperature under an argon atmosphere over three months.
11.
The final product had the following characteristics;
1H NMR
pdf (CDCl
3, 500 MHz) δ: 2.08 (s, 3 H), 3.06 (dd, 1 H,
J = 13.8, 4.3 Hz), 3.18 (dd, 1 H,
J = 13.8, 10.8 Hz), 3.56 (dqd, 1 H,
J = 10.8, 8.6, 4.1 Hz), 7.15–7.32 (m, 5 H);
13C NMR (CDCl
3, 125 MHz) δ: 31.6 (q,
JC-F = 1.8 Hz), 31.8 (q,
JC-F = 2.8 Hz), 57.4 (q,
JC-F = 24.9 Hz), 124.4 (q,
JC-F = 279.5 Hz), 127.0, 128.7, 128.8, 136.4, 201.3 (q,
JC-F = 1.5 Hz);
19F NMR (CDCl
3, 396 MHz) δ: −67.72 (d, 3 F,
J = 7.5 Hz); IR (KBr) cm
−1: 3033, 2942, 1731, 1606, 1499, 1457, 1422, 1362, 1301, 1263, 1161, 1115, 1081, 1505, 874, 747, 704; MS
m/
z: 216 (M
+); HRMS Calc. C
11H
11OF
3: 216.0762 (M
+), Found: 216.0763; Elemental Analysis Calc. for C
11H
11OF
3: C, 61.11; H, 5.13; F, 26.36. Found: C, 60.87; H, 5.04; F, 26.68.
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
Trifluoromethylated (CF
3) compounds constitute one of the most important classes of
fluorine-containing compounds, and there are many reports on trifluoromethylation reactions. However, the reactions for introducing a CF
3 group at the α-position of ketones are limited to trifluoromethylation of metal enolates of carbonyl compounds or imides,
2 electrophilic trifluoromethylation with calcogenium reagents,
3 and photochemical
4a and ultrasonic
4b reactions of enamines with CF
3I.
Recently, our group reported that α,β-unsaturated ketones react with
ethyl bromodifluoroacetate and Et
2Zn in the presence of a
rhodium catalyst to give unexpected products, in which either the CF
2COOEt group was introduced on the α-carbon of α,β-unsaturated ketones or the expected 1,2-addition product proceeded in good yields depending on the solvent.
5 On the basis of this result, we treated α,β-unsaturated ketones with
CF3I in the presence of Et
2Zn and RhCl(PPh
3)
3 to prepare α-CF
3 ketones.
6 This method was found to be superior to previous routes for synthesis of α-CF
3 ketones because it did not need special reagents, could be carried out under mild conditions, and provided the product in good yield. Moreover, trifluoromethylation at the α-position of α,β-unsaturated ketones had not been reported.
A mechanistic proposal is shown below (Figure 3).
6 A β-hydrogen atom in Et
2Zn appears to play an important role in this reaction because
dimethylzinc does not work at all.
Figure 3. Proposed Mechanism
Following the procedure described above, various α-CF3 ketones were obtained in good yields as shown in Table 1. The yields reported in the Table are based on reactions performed on a 2-mmol scale.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
4-Phenyl-3-buten-2-one; (122-57-6)
RhCl(PPh3)3: Rhodium, chlorotris(triphenylphosphine)-, (SP-4-2)-; (14694-95-2)
Trifluoroiodomethane; (2314-97-8)
Diethylzinc; (557-20-0)
4-Phenyl-3-(trifluoromethyl)butan-2-one:
2-Butanone, 4,4,4-trifluoro-3- (phenylmethyl)-; (808105-43-3)
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