Org. Synth. 2003, 80, 172
DOI: 10.15227/orgsyn.080.0172
PREPARATION AND USE OF A NEW DIFLUOROCARBENE REAGENT. TRIMETHYLSILYL 2-FLUOROSULFONYL-2,2-DIFLUOROACETATE: n-BUTYL 2,2-DIFLUOROCYCLOPROPANECARBOXYLATE
[(Cyclopropanecarboxylic acid, 2,2-difluoro-, butyl ester and Acetic acid, difluoro(fluorosulfonyl)-, trimethylsilyl ester)]
Submitted by W. R. Dolbier, Jr.
1, F. Tian, J.-X. Duan, and Q.-Y. Chen.
Checked by Victoria D. Bock, David P. Richardson, and Steven Wolff.
1. Procedure
Caution: Trimethylsilyl 2-fluorosulfonyl-2,2-difluoroacetate should be handled with care. Skin contact, which will cause painful burns and blistering, should be avoided. If such contact occurs, the affected area should be washed thoroughly with water and with sodium bicarbonate solution.
A. Trimethylsilyl 2-fluorosulfonyl-2,2-difluoroacetate. All glassware is oven-dried for about 1 hr prior to use. A 1-L, three-necked, round-bottomed flask is equipped with a magnetic stirrer, addition funnel with a nitrogen (N2) inlet, and water-cooled condenser with gas outlet. The gas outlet is connected by Tygon tubing to an empty 500-mL back-up trap, and then to an inverted 75-mm glass funnel outlet positioned just above a 1-L beaker containing 75 g of sodium bicarbonate (NaHCO3) in 500 mL water (to neutralize HCl and chlorotrimethylsilane from the reaction vessel) (Note 1). The flask is charged with 150 g of 2-fluorosulfonyl-2,2-difluoroacetic acid (0.84 mol) (Note 2). Then, with a slow N2 flow and cooling with an ice bath, 363 g of chlorotrimethylsilane (3.2 mol) (Notes 3, 4) is added dropwise with stirring over a 2 hr period. Upon completion of the addition, the mixture is allowed to warm to room temperature and is stirred with N2 bubbling for 24 hr. The product mixture is distilled to give 175 grams (83%) of trimethylsilyl 2-fluorosulfonyl-2,2-difluoroacetate (bp 52°C at 15 mm) (Notes 5, 6).
B. n-Butyl 2,2-difluorocyclopropanecarboxylate. A 500-mL, round-bottomed, three-necked flask is fitted with a magnetic stirrer, condenser, addition funnel, gas dispersion tube extending to the bottom of the flask, and gas outlet with a paraffin oil bubbler. The flask is charged with 200 mL of toluene, 0.4 g of sodium fluoride (0.06 eq), and 20 g of n-butyl acrylate (0.156 mol) (Notes 7, 8). The solution is heated to reflux and slow N2 bubbling is initiated with stirring for 1 hr. Trimethylsilyl 2-fluorosulfonyl-2,2-difluoroacetate (62.5 g, 0.31 mol, 1.6 eq) (Note 5) is added dropwise (Note 9). The mixture is heated for 8 hr, then cooled and filtered under vacuum filtration through a Celite pad (Note 10). Toluene is removed by simple distillation at atmospheric pressure, and the residue distilled at reduced pressure to obtain 15.4 g of n-butyl 2,2-difluorocyclopropanecarboxylate (55%) (bp 99-101°C at 58 mm) as a colorless liquid (Note 11).
2. Notes
1.
In order to avoid suction of the NaHCO
3 solution into the trap, the mouth of the funnel should not be submerged in the NaHCO
3 solution.
2.
2-Fluorosulfonyl-2,2-difluoroacetic acid can be obtained from Aldrich Chemical Co., Inc., Oakwood Products, Inc., or from FluoroTech, LLC (PO Box 13135, Gainesville, FL 32604).
3.
A 3.5-4 fold excess of
chlorotrimethylsilane is required for full conversion of the
2-fluorosulfonyl-2,2-difluoroacetic acid. Residual acid can be difficult to separate from the ester.
4.
Chlorotrimethylsilane (bp 55°C) was obtained from Aldrich Chemical Co., Inc. and used as received.
5.
Trimethylsilyl 2-fluorosulfonyl-2,2-difluoroacetate is moisture-sensitive and, if possible, should be prepared immediately before use in the next step.
6.
Trimethylsilyl 2-fluorosulfonyl-2,2-difluoroacetate is characterized as follows:
1H NMR (CDCl
3) δ: 0.40 ppm (s);
13C NMR, δ: −1.05 ppm (s), 112.22 (dt, J = 31.5, 299.0), 155.13 (t, J = 27.0);
19F NMR, δ: −103.74 ppm (2F, s), 40.58 (1F, s).
27.
Toluene (anhydrous), sodium fluoride (Reagent grade), and n-butyl acrylate (99+%) were obtained from Aldrich Chemical Co., Inc. and used as received.
8.
Other acrylate esters should function equally well in this synthesis. The n-butyl ester was specifically chosen because the boiling point of the product is sufficiently different from that of toluene, permitting convenient separation by distillation.
9.
Addition of the
trimethylsilyl 2-fluorosulfonyl-2,2-difluoroacetate should be slow at the beginning of the reaction, but can be gradually increased. A vigorous evolution of gas (CO
2 and SO
2) accompanies the early stages of addition, but will be barely distinguishable from the nitrogen flow at the end.
10.
Filtration through the Celite pad is recommended in order to remove small amounts of acrylate polymer.
11.
n-Butyl 2,2-difluorocyclopropanecarboxylate is characterized as follows:
1H NMR (CDCl
3) δ: 0.91 (3H, t, J = 7.32), 1.39 (2H, m), 1.62 (2H, m), 1.72 (1H, m), 2.04 (1H, m), 2.41 (1H,m), 4.15 (2H, q, J = 6.75);
19F NMR, δ: −126.50 (1F, m), −114.70 (1F,m);
13C NMR, δ: 13.49, 16.30 (t, J = 10.6), 18.92, 25.51 (t, J = 10.6), 30.43, 65.31, 110.6 (m), 166.57 ppm. The product obtained by the checkers was contaminated with small amounts of
n-butyl acrylate, which could not be removed by distillation.
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 present example provides a typical procedure for difluorocyclopropanation utilizing a new and highly versatile source of difluorocarbene.
3,4 This novel reagent,
trimethylsilyl 2-fluorosulfonyl-2,2-difluoroacetate, provides a convenient procedure for the synthesis of difluorocyclopropane compounds via addition of difluorocarbene to alkenes of highly variable nucleophilicity.
2 A relatively small excess of reagent is required for high yields, and even electrophilic alkenes, such as
n-butyl acrylate, provide acceptable yields of the difluorocyclopropane adduct. The reactivity and preparative utility of our reagent is probably comparable to Seyferth's reagent,
phenyl(trifluoromethyl)mercury,
5 but this latter substance is no longer commercially available and is both tedious and hazardous to prepare.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
n-Butyl 2,2-difluorocyclopropanecarboxylate:
Cyclopropanecarboxylic acid, 2,2-difluoro-, butyl ester (9); (260352-79-2)
Trimethylsilyl 2-fluorosulfonyl-2,2-difluoroacetate:
Acetic acid, difluoro(fluorosulfonyl)-, trimethylsilyl ester (9); (120801-75-4)
Chlorotrimethylsilane:
Silane, chlorotrimethyl- (8,9); (75-77-4)
2-Fluorosulfonyl-2,2-difluoroacetic acid:
Acetic acid, difluoro(fluorosulfonyl)- (8,9); (1717-59-5)
n-Butyl acrylate:
2-Propenoic acid, butyl ester (9); (141-32-2)
Sodium fluoride:
Sodium fluoride (NaF) (9); (7681-49-4)
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