α -Fluorination of β -dicarbonyl compounds using p -iodotoluene difluoride under neutral conditions

A selective introduction of a fluorine atom into the α -position of β -dicarbonyl compounds was achieved using p -iodotoluene difluoride. The reaction proceeded under mild conditions and monofluorination of β -ketoesters, ketoamides, and diketones selectively took place


Introduction
Direct substitution of α-hydrogen of β-dicarbonyl compounds into a fluorine atom is a most efficient method for the synthesis of α-fluoro-β-dicarbonyl compounds which have been used as building blocks for the preparation of biologically active compounds containing a fluorine atom. 1 Elemental fluorine (F 2 ) 2 or one of the many electrophilic fluorinating agents such as FClO 3 , 3 XeF 2 , 4 AcOF, 5 R f OF, 6 and CsSO 4 F 7 has been used for the fluorination of β-dicarbonyl compounds.However, most of these agents are highly aggressive, unstable and even explosive, and require special equipment and experience for safe handling.N-Fluorocompounds 8 have been developed as stable and effective fluorinating reagents of carbonyl compounds, but they need F 2 for their preparation and are expensive.We have studied the fluorination of organic compounds using p-iodotoluene difluoride (1) 9 which is not only easy to handle, but also accessible without hazardous F 2 and harmful Hg salts. 10Recently, we succeeded in the selective fluorination of βketoesters (2) using 1 and an HF-amine complex. 11Though 1 is a stable and safe compound, HFamine complexes are hazardous.Therefore, we continued to investigate the fluorination reaction of β-carbonyl compounds using 1 to find a more convenient method, and we found the fluorination of β-dicarbonyl compounds using 1 without the addition of the HF-amine complexes (Scheme 1).The fluorination of β-dicarbonyl compounds under neutral conditions is slow compared with that under acidic conditions.When the fluorination of ketoesters 2 using 1 was carried out in the presence of pyridine-9HF, the reaction was completed at room temperature in a few hours. 11On the other hand, under neutral conditions, the reaction of pentyl acetoacetate (2a) with 1 was sluggish at room temperature and only a trace of the fluorinated product (5a) was formed after 12 h.When the reaction was carried out at 40 °C in CH 2 Cl 2 , 2a was consumed in 10 h and 5a was obtained in 65% yield (Entry 1 in Table 1).Under the similar reaction conditions, various βketoesters (2a-d) were selectively monofluorinated, and difluoro products were not formed at all (Entries 1-4 in Table 1).The fluorination of β-ketoamides (3a-c) using 1 was also possible under neutral conditions, and monofluorinated products (6a-c) were obtained in good yield (Entries 5-7).

Table 2. Fluorination of β-diketones by 1
a Isolation yields based on 4 used and in parentheses, NMR yield.b 1 eq. of pyridine-9HF was added.
The fluorination reaction of β-diketones (4) was also examined.In the presence of the amine-HF complex, the reaction of β-diketones (4a,b) with 1 gave the desired monofluoro products (7a,b) in moderate yields with unidentifiable by-products (Entries 2 and 4 in Table 2).In the reaction of 4a with 1 under the neutral condition, the longer reaction time was required to consume 4a but the monofluoro product 7a could be obtained in good yield (Entry 1).Under similar conditions, α-unsubstituted β-diketones (4b-d) gave α-fluoro-β-diketones (7b-d) in good yield as shown in Table 2.

Experimental Section
General Procedures.IR spectra were recorded using a JASCO FT/IR-410. 1 H and 19 F NMR spectra were recorded in CDCl 3 on a JEOL JNM-A400 II FT NMR and chemical shifts, δ, are referred to TMS ( 1 H) and CFCl 3 ( 19 F) respectively.High-resolution mass spectra were taken at the Center for Instrumental Analysis, Hokkaido University.silica gel 60N of Kanto Chemical Co., Inc. was used for column chromatography and Merck Silica gel 60 F 254 was used for TLC analysis.1 was prepared from iodotoluene as reported before. 10Ketoesters 2a-c, ketoamide 3a, and diketones 4a-b were purchased from Tokyo Kasei Kogyo Co., Ltd. and used without purification.Pyridine-9HF was prepared from anhydrous HF and pyridine according to the literature. 12Ketoamides 3b-c were prepared from diketene and the corresponding amines according to the literature. 13Ketoester 2d 14 and diketones 4c, d 15 were prepared according to the literature.

General procedure for the synthesis of α-fluoro-β-ketoesters (5a-d)
A CH 2 Cl 2 solution (5 ml) of 2a-d (1 mmol) and 1 (282 mg, 1.1 mmol) in a Teflon ® vessel with a screw-cap was stirred at 40 °C.After the reaction, the mixture was poured into 20 ml of aqueous NaHCO 3 and extracted with ether (20 ml x 3).The combined organic layers were dried over MgSO

General procedure for the synthesis of α-fluoro-β-ketoamides (6a-c)
A CH 2 Cl 2 solution (5 ml) of 3a-c (1 mmol) and 1 (282 mg, 1.1 mmol) in a Teflon ® vessel with a screw-cap was stirred at 40 °C.After the reaction, the mixture was concentrated under reduced pressure and purification by column chromatography (silica gel/hexane-ether) gave 6a-c.General procedure for the synthesis of α-fluoro-β-diketones (7a-d) under the neutral conditions A CHCl 3 solution (2 ml) of 4a-e (1 mmol) and 1 (333 mg, 1.3 mmol) in a Teflon ® vessel with a screw-cap was stirred at room temperature.After the reaction, the mixture was poured into water and extracted with ether (20 ml x 3).The combined organic layers were dried over MgSO 4 , and concentrated under reduced pressure.Purification by column chromatography (silica gel/hexaneether) gave 7a-e.General procedure for the synthesis of α-fluoro-β-diketones (7a,b) in the presence of pyridine-9HF To a CH 2 Cl 2 solution (4 ml) of 4a,b (1 mmol) in a Teflon ® vessel were added 1 (333 mg, 1.3 mmol) and pyridine-9HF (259mg, 1 mmol) and the mixture was stirred at room temperature.After the reaction, the mixture was poured into aqueous NaHCO 3 and extracted with ether (20 ml x 3).The combined organic layers were washed with water, aqueous CuSO 4 , and water successively, dried over MgSO 4 , and concentrated under reduced pressure.The purification by column chromatography (silica gel/hexane-ether) gave 7a,b.