通过1, 3-二芳基-1, 3-二酮合成α, α, γ, γ-四氟-β-羟基酮和α-氟代苯乙酮

引用本文: 鲍堃, 危俊, 盛荣. 通过1, 3-二芳基-1, 3-二酮合成α, α, γ, γ-四氟-β-羟基酮和α-氟代苯乙酮[J]. 有机化学, 2020, 40(4): 930-937. doi: 10.6023/cjoc201910014 shu

Citation: Bao Kun, Wei Jun, Sheng Rong. Synthesis of α, α, γ, γ-Tetrafluoro-β-hydroxy Ketones and α-Fluoroacetophenones via 1, 3-Diaryl-1, 3-diketones[J]. Chinese Journal of Organic Chemistry, 2020, 40(4): 930-937. doi: 10.6023/cjoc201910014 shu

通过1, 3-二芳基-1, 3-二酮合成α, α, γ, γ-四氟-β-羟基酮和α-氟代苯乙酮

鲍堃 ^a,b, ,
危俊 ^b, ,
盛荣 ^{b,
,}

a.
浙江工业大学长三角绿色制药协同创新中心杭州 310014
b.
浙江大学药学院杭州 310058

通讯作者: 盛荣, shengr@zju.edu.cn

摘要: α, α, γ, γ-四氟-β-羟基酮和α-氟代苯乙酮两类化合物被广泛运用于有机化学、农业化学以及制药等领域.开发了一种从1, 3-二芳基-1, 3-二酮合成α, α, γ, γ-四氟-β-羟基酮和α-氟代苯乙酮的温和且有效的方法.通过改变反应条件, 可以分别以中等至良好的产率获得两种不同的产物.

关键词:

English

Synthesis of α, α, γ, γ-Tetrafluoro-β-hydroxy Ketones and α-Fluoroacetophenones via 1, 3-Diaryl-1, 3-diketones

Bao Kun ^a,b, ,
Wei Jun ^b, ,
Sheng Rong ^{b,
,}

a.
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014
b.
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058

Corresponding author: Sheng Rong, E-mail:shengr@zju.edu.cn

Received Date: 11 October 2019
Revised Date: 07 December 2019
Available Online: 25 April 2020

Abstract: α, α, γ, γ-Tetrafluoro-β-hydroxy ketones and α-fluoroacetophenones are widely used in the fields of organic chemistry, agrochemicals, and pharmaceuticals. A mild and excellent method to synthesize α, α, γ, γ-tetrafluoro-β-hydroxy ketones and α-fluoroacetophenones via various 1, 3-diaryl-1, 3-diketones has been developed. With the modification of reaction conditions, two different products could be obtained in moderate to good yields, respectively.

Key words:

α, α, γ, γ-tetrafluoro-β-hydroxy ketones
/ α-fluoroacetophenones
/ 1, 3-diaryl-1, 3-diketones

1. Introduction

Organofluorine compounds are widely applied in agrochemical, ^[1] pharmaceutical, ^[2] and material^[3] fields because of the distinctive function of fluorine atom in the molecules.^[4] Especially in medicinal chemistry, the introduction of fluorine or fluoro-containing moiety into molecules can optimize the pharmacological and pharmacokinetic property^[5] of compounds. There are about 10%~12% known drugs^[6] in clinic containing fluorine atom, such as betamethasone, fluconazole, roflumilast and so on (Figure 1). Therefore, over the past few years, the development of efficient and novel methods to synthesize organofluorine compounds has become a hot topic in organic chemistry.

图 1

图 1. Representative fluorine-containing drugs

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1, 3-Diketones are stable and widely available reagents in organic chemistry.^[7] They usually served as useful building diverse heterocycles, ^[8] such as 2H-pyrans, ^[9] indoles, ^[10] blocks in organic synthesis, especially in the construction of pyridines, ^[11] and so on. In addition, 1, 3-diketones are easily fluorinated to get 2-fluoro-1, 3-diketones or 2, 2-difluoro-1, 3-diketones, which are used to prepare various organofluorine compounds.^[12] For example, Zhang’s group^[13] reported an efficient one-pot synthetic method of 3-fluoroflavones using in situ prepared 2-fluoro-1, 3- diketones (Scheme 1a). Yi’s group^[14] revealed that 2- fluoro-1, 3-diketones and 2, 2-difluoro-1, 3-diketones can be used as nucleophilic mono(di)-fluoromethylation reagents, followed by reacting with diaryl disulfides, aldehyde and N-benzylisatins to achieve α-thioaryl-α, α-difluoroaceto- phenones, α-fluoro-α, β-unsaturated ketones, and 3-difluo- roalkyl-3-hydroxyoxindoles, respectively (Scheme 1b). More recently, Browne’s group^[15] described the mechanochemistry reaction of 2, 2-difluoro-1, 3-diketones with phenyl disulfide using ball-milling, in which difluorothioether or tetrafluorohydroxyketone derivatives could be prepared in good yields (Scheme 1c).

图式 1

图式 1. Application of mono(di)-fluoro-1, 3-diketones

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2. Results and discussion

Due to that the ball-milling is not widely available in organic chemistry laboratory, we tried to perform the reaction of 2, 2-difluoro-1, 3-diphenyl-1, 3-propanedione (1a) with Cs₂CO₃ using general stirring method. As expected, the desired tetrafluorohydroxyketone (2a) can be obtained in 31% yield when acetonitrile was used as solvent (Table 1, Entry 1). Then, other different solvents, including CH₂Cl₂, N, N-dimethylformamide (DMF), tetrahydrofuran (THF), 1, 4-dioxane and dimethyl sulfoxide (DMSO) were screened to improve the yields of corresponding product 2a (Table 1, Entries 2~6), and the results showed that DMSO was the optimal one among all these solvents with yield of 56% (Table 1, Entry 6). The replacement of Cs₂CO₃ with other bases, including K₂CO₃, KOH, EtONa, NaOAc and 1, 4-diazabicyclo[2.2.2]octane (DABCO) cannot improve the yields of 2a (Table 1, Entries 7~11). Interestedly, the neat reaction of 1a and cesium carbonate at room temperature for 10 h can produce 2a in excellent yield of 82% (Table 1, Entry 12).

表 1

表 1 Optimization of reaction conditions^a

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Entry	Solvent	Base	Yield^b/%
1	CH₃CN	Cs₂CO₃	31
2	CH₂Cl₂	Cs₂CO₃	12
3	DMF	Cs₂CO₃	39
4	THF	Cs₂CO₃	51
5	1, 4-Dioxane	Cs₂CO₃	49
6	DMSO	Cs₂CO₃	56
7	DMSO	K₂CO₃	18
8	DMSO	KOH	0
9	DMSO	EtONa	26
10	DMSO	NaOAc	49
11	DMSO	DABCO	13
12	Solvent-free	Cs₂CO₃	82
^a Reaction condition: 1a (0.5 mmol) and base (1.5 mmol) in 2 mL of solvent stirred at room temperature for 10 h; ^b isolated yields.

With the optimized conditions in hand, the substrate scope of the reaction was investigated with a variety of 2, 2-difluoro-1, 3-diaryl-1, 3-diketones, and the results are summarized in Table 2. In general, for the para- or meta-sub- stituted substrates, the electronic effect did not affect the yields of products obviously, both electron-donating and electron-withdrawing substituted substrates 1b~1i afford the desired products 2b~2i in moderate to good yields (50%~82%). The heteroaryl substrate 1j was also suitable for this reaction and gave the corresponding product 2j in 60% yield, while the ortho-methoxy substituted substrate 1k only yielded trace of product 2k, indicating the importance of steric effect.

表 2

表 2 Scope of the 2, 2-difluoro-1, 3-diketones^a

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Entry	R	Yield^b/%
1	Ph (1a)	82
2	4-FC₆H₄ (1b)	76
3	4-ClC₆H₄ (1c)	72
4	4-MeC₆H₄ (1d)	50
5	4-CF₃C₆H₄ (1e)	71
6	4-CNC₆H₄ (1f)	68
7	4-BrC₆H₄ (1g)	65
8	3-MeOC₆H₄ (1h)	53
9	3-ClC₆H₄ (1i)	52
10	Thiophene (1j)	60
11	2-MeOC₆H₄ (1k)	Trace
^a Reaction condition: 1 (0.5 mmol), Cs₂CO₃ (1.5 mmol), solvent-free, r.t. for 10 h. ^b isolated yields.

Then, asymmetric substrate 1m with different substituents on the phenyl ring was investigated under the standard conditions (Scheme 2A). The main product 2m₁ which containing electron-donating substituents on the phenyl ring was obtained in 35% yield, and trace amount of 2m₃ or 2m₄ was detected in the reaction mixture with LC-MS analysis. The possible product 2m₂ cannot be detected in the mixture. Similarly, when another asymmetric substrate 1n was performed under the same conditions (Scheme 2B), only product 2n₁, which containing electron-donating substituents on the phenyl ring, was separated as main product, other three possible products 2n₂, 2n₃ and 2n₄ cannot be found in the reaction mixture. These results show that the main way of carbon-carbon bond cleavage in this reaction was path b, which produced more nucleophilic difluoroenolate intermediates, as shown in Scheme 2C.

图式 2

图式 2. Reaction of asymmetric aryl substituted 2, 2-difluoro-1, 3-diaryl-1, 3-diketones

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α-Fluoroacetophenones are frequently found in many bioactive molecules and can act as important intermediates in many organic reactions.^[16] Many methods have been developed in the past few decades to get α-fluoroaceto- phenones. In general, they can be classified into two strategies.^[17] The first one involves the introduction of fluorine atom into substrates with electrophilic fluorinating reagents, including N-fluorobenzenesulfonimide (NFSI), and Selectfluor^®.^[18] The second approach is the nucleophilic substitution of substrate with fluoride anion using KF/Ph₃SnF, KF and so on.^[19] We envisioned that 1, 3-diaryl-1, 3-diketones can also provide α-fluoroacetogation through decarbonyl fluorination.

Our investigation started with the reaction of 1, 3-di- phenylpropane-1, 3-dione (3a) with Selectfluor^® under various conditions. Firstly, Hu’s protocol^[20] for the decarboxylative fluorination of β-ketoacids in the CH₃CN/H₂O mixed solvent system was tried. As expected, 11% yield of desired product 4a can be detected in ¹⁹F NMR (Table 3, Entry 1). The reaction can hardly proceed when the water was removed (Table 3, Entry 2). Thus, the different co- solvents were studied for this transformation and the results showed that CH₃CN/H₂O (V:V＝9:1) was optimal to furnish 4a in 25% yield (Table 3, Entry 3). Then, the temperature of reaction mixture was raised and the yields of 4a was improved accordingly (Table 3, Entries 5~7). Then, different bases and the equivalent of base were evaluated. When Cs₂CO₃ was replaced by other bases (KOH, K₂CO₃, NaOAc), a decrease in the yield of 4a was observed (Table 3, Entries 8~10), and 1.5 equiv. of Cs₂CO₃ is optimal for this reaction with yield of 69% (Table 3, Entry 13). In summary, these results showed that the optimal conditions for this reaction as follows: the mixture of 3a (1.0 equiv.) and Selectfluor^® (1.05 equiv.) was dissolved in a mixture of 2.0 mL of CH₃CN/H₂O (V:V＝9:1) and refluxed for 2.5 h, followed by the addition of 1.5 equiv. of Cs₂CO₃ and refluxed for another 5 h.

表 3

表 3 Optimization of reaction conditions^a

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Entry	Solvent (volume ratio)	t/℃	Base (equiv.)	Yield^b/%
1	CH₃CN/H₂O (20:1)	r.t.	Cs₂CO₃ (3.0)	11
2	CH₃CN	r.t.	Cs₂CO₃ (3.0)	Trace
3	CH₃CN/H₂O (9:1)	r.t.	Cs₂CO₃ (3.0)	25
4	CH₃CN/H₂O (5:1)	r.t.	Cs₂CO₃ (3.0)	20
5	CH₃CN/H₂O (9:1)	40	Cs₂CO₃ (3.0)	29
6	CH₃CN/H₂O (9:1)	60	Cs₂CO₃ (3.0)	43
7	CH₃CN/H₂O (9:1)	Reflux	Cs₂CO₃ (3.0)	53
8	CH₃CN/H₂O (9:1)	Reflux	KOH (3.0)	45
9	CH₃CN/H₂O (9:1)	Reflux	K₂CO₃ (3.0)	43
10	CH₃CN/H₂O (9:1)	Reflux	NaOAc (3.0)	10
11	CH₃CN/H₂O (9:1)	Reflux	Cs₂CO₃ (4.0)	41
12	CH₃CN/H₂O (9:1)	Reflux	Cs₂CO₃ (2.0)	56
13	CH₃CN/H₂O (9:1)	Reflux	Cs₂CO₃ (1.5)	69
14	CH₃CN/H₂O (9:1)	Reflux	Cs₂CO₃ (1.0)	52
^a Reaction condition: The mixture of 3a (0.2 mmol) and Selectfluor^® (0.21 mmol) was stirred with various solvents (2.0 mL) for 2.5 h at different temperature, followed by the addition of various bases. The resulting mixture was continuously stirred for 5 h; ^byields were determined by ¹⁹F NMR using PhCF₃ as an internal standard.

Then, the reaction scope of 1, 3-diaryl-1, 3-diketones 3 was surveyed, and the results are summarized in Table 4. In general, the electronic effect on phenyl ring did not affect the yields obviously in this reaction. Different substituent on the phenyl ring, both electron-donating groups (methy, methoxy) and electron-withdrawing groups (fluoro, chloro, cyano, trifluoromethyl) can proceed this reaction smoothly and obtain corresponding products in good yields (53%~75%). The ortho-substituent on the aromatic ring of 1, 3-diaryl-1, 3-diketones (3k) provided relatively lower yields of the desired products in comparison with the meta-, para-substituted 1, 3-diaryl-1, 3-diketones (3h, 3l), probably due to the steric effects. The heterocycle substrate 3j was also suitable for this transformation and gave the respective product 4j in good yield.

表 4

表 4 Scope of the 1, 3-diaryl-1, 3-diketones^a

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Entry	R	Yield^b/%
1	Ph (3a)	68
2	4-FC₆H₄ (3b)	65
3	4-ClC₆H₄ (3c)	75
4	4-MeC₆H₄ (3d)	69
5	4-CF₃C₆H₄ (3e)	68
6	4-CNC₆H₄ (3f)	70
7	4-BrC₆H₄ (3g)	66
8	3-MeOC₆H₄ (3h)	61
9	3-ClC₆H₄ (3i)	61
10	Thiophene (3j)	65
11	2- MeOC₆H₄ (3k)	53
12	4-MeOC₆H₄ (3l)	62
^a Reaction condition: 3 (0.50 mmol), Selectfluor^® (0.53 mmol) was dissolved in 4.0 mL CH₃CN/H₂O (9:1) and refluxed for 2.5 h, after which Cs₂CO₃ (0.75 mmol) was added. The resulting mixture was refluxed for 5 h. ^b isolated yields.

The asymmetric substrates of 3m and 3n with different susbstituents on phenyl ring were also investigated in this reaction (Scheme 3). We found that the main products were 4d and 4l, respectively. The other possible product 4f cannot be detected in the reaction system. These results showed that asymmetric substrates could selectively generate α-fluoroacetophenones which containing electron-donating substituents on the phenyl ring.

图式 3

图式 3. Reaction of asymmetric aryl substituted1, 3-diaryl- 1, 3-diketones

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To further demonstrate the practicability and effectiveness of this methodology, two gram-scale synthesis has been performed as followed. When 4.0 mmol of 2, 2- difluoro-1, 3-diphenyl-1, 3-propanedione (1a) was reacted with 12.0 mmol of Cs₂CO₃, the corresponding product 2a can be obtained with yield of 73%, which was consistent with previous data (82%). We also carried out the gram- scale synthesis of 4a and gave yield of 61%, which was consistent with previous data (68%).

We then turned our attention on the mechanistic features of this reaction. When 1n was used as substrate under standard conditions, a side-product was found and confirmed as 2, 2-difluoro-1-(4-methoxyphenyl)ethan-1-one (2n') by ¹H NMR spectrum. Therefore, we proposed a plausible mechanism^[15] for the synthesis of 2a in Scheme 4. Initially, 2, 2-difluoro-1, 3-diphenyl-1, 3-propanedione (1a) is attacked by Cs₂CO₃ to form α, α-difluoroenolate intermediate 7, then 7 was protonated to form α, α-difluoro- acetophenone 8. The aldol reaction between 7' and 8 gave the intermediate 9 and protonated into product 2a.

图式 4

图式 4. Proposed mechanism for the synthesis of 2a

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We proposed the possible mechanism for the synthesis of 4a as shown in Scheme 5. Firstly, 1, 3-diphenylpropane-1, 3- dione (3a) was transformed to enol intermediate 10, which was fluorinated by Selectfluor to form intermediate 11. Then, intermediate 11 was attacked by Cs₂CO₃/H₂O to yield α-fluoroacetophenone 4a.

图式 5

图式 5. Proposed mechanism for the synthesis of 4a

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3. Conclusions

In summary, we have demonstrated a simple and efficient method to prepare α, α, γ, γ-tetrafluoro-β-hydroxy ketones and α-fluoroacetophenones from various 1, 3-diaryl-1, 3-diketones. With the modification of reaction conditions, two different products could be obtained in moderate to good yields, respectively.

4. Experimental

4.1 General methods

All reactions were monitored by thin layer chromatography purchased from commercial suppliers. And the spots were visualized using UV radiation (254 nm). Flash chromatography was performed on 200~300 mesh silica gel. ¹H NMR spectra were recorded on 400 or 500 MHz (100 or 126 MHz for ¹³C NMR, 376 or 471 MHz for ¹⁹F NMR) Zhongke-Niujin WNMR-I-400 or BRUCKER AVANCE III 500 NMR spectrometer with DMSO-d₆ or CDCl₃ as the solvent and tetramethylsilane (TMS) as the internal standard. Chemical shifts were reported downfield from TMS at δ 0.00 and referenced to CDCl₃ (δ 7.26 in ¹H NMR and δ 77.02 in ¹³C NMR) and DMSO-d₆ (δ 2.50 in ¹H NMR and δ 39.52 in ¹³C NMR). High resolution MS (HRMS) was performed on an Agilent 6224 TOF LC/MS spectrometer. All commercially available reagents and solvents were used as received unless otherwise specified. The substrates were readily prepared according to known methods. Substrates 1 and 3 were prepared according to literature methods.^[21]

4.2 General procedure for the synthesis of α, α, γ, γ- tetrafluoro-β-hydroxy ketones 2a~2k

The mixture of 2, 2-difluoro-1, 3-diphenyl-propane-1, 3- dione (1a) (0.5 mmol, 1.0 equiv.) and cesium carbonate (1.5 mmol, 3.0 equiv.) was stirred in Schlenk tube by magnetic stirrer at room temperature for 10 h. Then, the reaction was extracted with ethyl acetate (15 mL×3), the combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo to give the crude product, which was purified carefully by column chromatography, ethyl acetate and petroleum ether as eluent to afford product 2a as yellow oil. Compounds 2b~2k were prepared in the similar manner.

2, 2, 4, 4-Tetrafluoro-3-hydroxy-1, 3-diphenylbutan-1-one (2a): 82% yield, yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 7.96 (d, J＝8.5 Hz, 2H), 7.66~7.61 (m, 3H), 7.46 (t, J＝7.5 Hz, 2H), 7.42~7.39 (m, 3H), 6.50 (t, J_H—F＝54.5 Hz, 1H), 4.20 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 190.67 (t, J＝29.7 Hz), 134.76, 132.56 (d, J＝10.7 Hz), 130.33 (t, J＝3.0 Hz), 129.33, 128.62, 128.46, 126.87, 117.14 (t, J_C—F＝267.4 Hz), 115.93 (t, J_C—F＝250.6 Hz), 78.24 (t, J＝23.1 Hz); ¹⁹F NMR (471 MHz, CDCl₃) δ: -105.11~-106.91 (m), -128.36~-130.64 (m). ESI-HRMS calcd for C₁₆H₁₂F₄O₂Na [M+Na]⁺ 335.0666, found 335.0671.

2, 2, 4, 4-Tetrafluoro-1, 3-bis(4-fluorophenyl)-3-hydroxy-butan-1-one (2b): 76% yield, yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 8.04~8.01 (m, 2H), 7.65~7.62 (m, 2H), 7.16~7.12 (m, 2H), 7.11~7.07 (m, 2H), 6.47 (t, J_H—F＝54.5 Hz, 1H), 4.28 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 188.84 (t, J＝29.7 Hz), 167.79, 165.72, 164.29, 162.31, 133.51 (dt, J＝10.0, 3.7 Hz), 129.05 (d, J＝8.1 Hz), 128.78 (q, J＝2.6 Hz), 128.09 (t, J＝2.9 Hz), 117.07 (t, J_C—F＝267.0 Hz), 116.17, 116.00, 115.77 (t, J_C—F＝250.9 Hz), 115.59, 115.42, 77.98 (t, J＝22.9 Hz); ¹⁹F NMR (376 MHz, DMSO-d₆) δ: -103.26, -105.49~-107.79 (m), -113.16, -127.30~-130.43 (m). ESI-HRMS calcd for C₁₆H₁₀F₆O₂Na[M+Na]⁺ 371.0477, found 371.0477.

1, 3-Bis(4-chlorophenyl)-2, 2, 4, 4-tetrafluoro-3-hydroxy-butan-1-one (2c): 72% yield, yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 7.93 (d, J＝8.5 Hz, 2H), 7.59 (d, J＝8.5 Hz, 2H), 7.46~7.43 (m, 2H), 7.40~7.37 (m, 2H), 6.45 (t, J_H—F＝54.5 Hz, 1H), 4.22 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 189.16 (t, J＝30.0 Hz), 141.86, 135.72, 131.78 (t, J＝3.7 Hz), 130.74 (t, J＝2.0 Hz), 130.59 (t, J＝2.4 Hz), 129.12, 128.71, 128.39, 116.94 (t, J_C—F＝267.2 Hz), 115.63 (t, J_C—F＝251.1 Hz), 77.98 (t, J＝23.3 Hz); ¹⁹F NMR (376 MHz, DMSO-d₆) δ: -105.58~-108.16 (m), -127.21~-130.40 (m). ESI-HRMS calcd for C₁₆H₁₀Cl₂F₄O₂Na [M+Na]⁺ 402.9886, found 402.9890.

2, 2, 4, 4-Tetrafluoro-3-hydroxy-1, 3-di-p-tolylbutan-1-one (2d): 50% yield, yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 7.88 (d, J＝8.5 Hz, 2H), 7.53 (d, J＝8.0 Hz, 2H), 7.25 (d, J＝8.0 Hz, 2H), 7.21 (d, J＝8.5 Hz, 2H), 6.46 (t, J_H—F＝ 54.5 Hz, 1H). 4.27 (s, 1H), 2.41 (s, 3H), 2.34 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ: 190.26 (t, J＝29.6 Hz), 146.23, 139.20, 130.58 (t, J＝3.4 Hz), 129.94 (t, J＝2.4 Hz), 129.59, 129.37, 129.18, 126.76, 117.13 (t, J_C—F＝267.0 Hz), 115.96 (t, J_C—F＝250.4 Hz), 78.19 (t, J＝22.9 Hz), 21.88, 21.13; ¹⁹F NMR (376 MHz, DMSO-d₆) δ: -104.90~-106.80 (m), -128.32~-30.78 (m). ESI-HRMS calcd for C₁₈H₁₆F₄O₂Na[M+Na]⁺ 363.0979, found 363.0977.

2, 2, 4, 4-Tetrafluoro-3-hydroxy-1, 3-bis(4-(trifluorome-thyl)phenyl)butan-1-one (2e): 71% yield, yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 8.08 (d, J＝8.0 Hz, 2H), 7.80 (d, J＝8.0 Hz, 2H), 7.74 (d, J＝8.5 Hz, 2H), 7.69 (d, J＝8.0 Hz, 2H), 6.51 (t, J_H—F＝54.5 Hz, 1H), 4.17 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 189.41 (t, J＝30.0 Hz), 136.34 (q, J＝33.1 Hz), 136.04, 135.15, 132.17 (q, J＝32.9 Hz), 130.71 (t, J＝3.5 Hz), 127.56, 125.78 (q, J＝3.8 Hz), 125.52 (q, J＝3.8 Hz), 124.86 (d, J＝65.5 Hz), 122.69 (d, J＝66.2 Hz), 117.01 (t, J_C—F＝267.2 Hz), 115.62 (t, J＝251.4 Hz), 78.17 (t, J＝23.2 Hz); ¹⁹F NMR (376 MHz, DMSO-d₆) δ: -61.33(s), -61.96 (s), -105.75~-109.35 (m), -126.80~-130.37 (m). ESI-HRMS calcd for C₃₆H₁₉F₂₀O₄ [2M-H]^- 895.0969, found 895.0973.

1, 3-Bis(4-cyano)-2, 2, 4, 4-tetrafluoro-3-hydroxybutan-1-one (2f): 68% yield, yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 8.10 (d, J＝8.0 Hz, 2H), 7.81~7.77 (m, 4H), 7.74~7.72 (m, 2H), 6.49 (t, J_H—F＝54.5 Hz, 1H), 4.22 (s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 189.22 (t, J＝30.5 Hz), 137.41, 135.67 (t, J＝2.4 Hz), 132.81, 132.56, 131.10 (t, J＝3.5 Hz), 128.27, 118.46, 118.40, 117.72, 117.21 (t, J_C—F＝267.0 Hz), 115.75 (t, J_C—F＝251.2 Hz), 114.05, 78.48 (t, J＝23.4 Hz); ¹⁹F NMR (376 MHz, DMSO-d₆) δ: -105.38~-108.97 (m), -127.01~-130.31 (m). ESI- HRMS calcd for C₁₈H₉F₄N₂O₂[M-H]^- 361.0606, found 361.0602.

1, 3-Bis(4-bromophenyl)-2, 2, 4, 4-tetrafluoro-3-hydro-xybutan-1-one (2g): 65% yield, yellow oil. ¹H NMR (500 MHz, DMSO-d₆) δ: 7.90 (d, J＝4.0 Hz, 2H), 7.88 (s, 1H), 7.79 (d, J＝8.5 Hz, 2H), 7.65 (d, J＝8.5 Hz, 2H), 7.52 (d, J＝8.5 Hz, 2H), 6.94 (t, J_H—F＝53.0 Hz, 1H); ¹³C NMR (126 MHz, DMSO-d₆) δ: 187.91 (t, J＝27.5 Hz), 132.39, 131.69 (t, J＝3.4 Hz), 131.25, 130.51, 128.93, 128.47, 122.24, 118.22 (t, J_C—F＝264.9 Hz), 115.49 (t, J_C—F＝248.5 Hz), 76.67 (t, J＝23.6 Hz); ¹⁹F NMR (471 MHz, DMSO-d₆) δ: -104.93~-107.10 (m), -127.74~-130.51 (m). ESI-HRMS calcd for C₁₆H₁₀Br₂F₄O₂Na [M+Na]⁺: 490.8876, found 490.8880.

2, 2, 4, 4-Tetrafluoro-1, 3-bis(3-methoxy)-3-hydroxybutan-1-one (2h): 53% yield, yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 7.58 (d, J＝8.0 Hz, 1H), 7.43 (t, J＝2.0 Hz 1H), 7.36 (t, J＝8.0 Hz, 1H), 7.32 (t, J＝8.0 Hz, 1H), 7.22~7.19 (m, 2H), 7.17~7.15 (m, 1H), 6.93~6, 91 (m, 1H), 6.49 (t, J_H—F＝54.5 Hz), 4.31 (s, 1H) 3.81 (s, 3H), 3.78 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ: 190.08 (t, J＝29.5 Hz), 159.45 (d, J＝13.7 Hz), 133.88, 133.57 (t, J＝2.4 Hz), 129.44, 129.33, 122.84 (t, J＝4.3 Hz), 121.28, 118.83, 117.10 (t, J_C—F＝267.6 Hz), 115.70 (t, J_C—F＝250.6 Hz), 114.51, 114.15 (t, J＝2.9 Hz), 112.85, 77.97 (t, J＝23.2 Hz), 55.28, 55.1; ¹⁹F NMR (471 MHz, CDCl₃) δ: -105.12~-106.70 (m), -128.58~-130.57 (m). ESI-HRMS calcd for C₁₈H₁₆F₄NaO₄ [M+Na]⁺ 395.0877, found 395.0880.

1, 3-Bis(3-chlorophenyl)-2, 2, 4, 4-tetrafluoro-3-hydroxy-butan-1-one (2i): 52% yield, yellow oil. ¹H NMR (500 MHz, DMSO-d₆) δ: 7.99 (d, J＝8.5 Hz, 2H), 7.90 (s, 1H), 7.64~7.62 (m, 2H), 7.60 (d, J＝8.5 Hz, 2H), 7.51~7.48 (m, 2H), 6.94 (t, J_H—F＝53.5 Hz, 1H); ¹³C NMR (126 MHz, DMSO-d₆) δ: 188.18 (t, J＝28.1 Hz), 139.59, 134.01, 132.45, 132.16, 131.85, 129.16, 128.78, 128.07, 118.78 (t, J_C—F＝265.2 Hz), 116.04 (t, J_C—F＝248.3 Hz), 77.12 (t, J＝22.7 Hz); ¹⁹F NMR (471 MHz, DMSO-d₆) δ: -105.73~-108.14 (m), -127.35~-130.34 (m). ESI-HRMS calcd for C₁₆H₁₀Cl₂F₄O₂Na [M+Na]⁺ 402.9886, found 402.9885.

2, 2, 4, 4-Tetrafluoro-3-hydroxy-1, 3-di(thiophen-2-yl)-butan-1-one (2j): 60% yield, yellow oil. ¹H NMR (500 MHz, DMSO-d₆) δ: 8.20 (d, J＝3.5 Hz, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.60 (d, J＝4.0 Hz, 1H), 7.29 (t, J＝4.5 Hz, 1H), 7.26 (d, J＝3.5 Hz, 1H), 7.09 (dd, J＝5.0, 3.5 Hz, 1H), 6.72 (t, J_H—F＝54.0 Hz, 1H); ¹³C NMR (126 MHz, DMSO-d₆) δ: 181.40 (t, J＝29.0 Hz), 139.49, 138.82, 137.88 (t, J＝5.5 Hz), 136.63, 129.82, 127.94, 127.77, 127.60, 118.62 (t, J_C—F＝264.5 Hz), 115.78 (t, J_C—F＝250.5 Hz), 77.21 (t, J＝24.4 Hz); ¹⁹F NMR (471 MHz, DMSO-d₆) δ: -108.14~-109.72 (m), -127.08~-130.29 (m). ESI-HRMS calcd for C₁₂H₈F₄O₂S₂Na [M+Na]⁺ 346.9794, found 346.9798.

4.3 General procedure for the synthesis of α-fluoro- acetophenone 4a~4l

To a solution of 1, 3-diphenylpropane-1, 3-dione (3a) (0.5 mmol, 1.0 equiv.) in 4.0 mL of CH₃CN/H₂O (V:V＝9:1) was added Selectfluor® (0.53 mmol, 1.05 equiv.), the resulting solution was refluxed for 2.5 h. After that, cesium carbonate (0.75 mmol, 1.5 equiv.) was added to the solution and refluxed for 5 h. Then the reaction system was concentrated under reduced pressure and extracted with ethyl acetate (20 mL×3). The combined organic layer was dried over anhydrous sodium sulphate, filtered and con- centrated under reduced pressure. The residue was subjected to the column chromatography using ethyl acetate and petroleum ether as eluent to give product 2-fluoro-1-phenylethan-1-one (4a) in 68% yield. Other α-fluoroacetophenones 4b~4l were prepared in similar manner.

2-Fluoro-1-phenylethanone (4a):^[22] 68% yield, yellow oil. ¹H NMR (500 MHz, DMSO-d₆) δ: 7.90~7.88 (m, 2H), 7.70 (tt, J＝7.5, 1.5 Hz, 1H), 7.57~7.54 (m, 2H), 5.87 (d, J_H—F＝46.5 Hz, 2H); ¹³C NMR (126 MHz, DMSO-d₆) δ: 193.90 (d, J＝14.5 Hz), 133.99, 133.50, 128.90, 127.58 (d, J＝1.4 Hz), 84.68 (d, J_C—F＝176.4 Hz); ¹⁹F NMR (471 MHz, DMSO-d₆) δ: -232.92 (t, J＝46.6 Hz).

2-Fluoro-1-(4-fluorophenyl)ethanone (4b):^[24] 65% yield, colorless solid. m.p. 49~51 ℃ (lit.^[23] m.p. 47~49 ℃); ¹H NMR (500 MHz, DMSO-d₆) δ: 7.99~7.97 (m, 2H), 7.41~7.37 (m, 2H), 5.85 (d, J_H—F＝46.0 Hz, 2H); ¹³C NMR (126 MHz, DMSO-d₆) δ: 193.06 (d, J＝14.5 Hz), 166.86 (d, J_C—F＝253.0 Hz), 131.21 (d, J＝1.4 Hz), 131.14 (d, J＝1.3 Hz), 130.77 (d, J＝2.8 Hz), 116.58, 116.40, 85.05 (d, J_C—F＝176.5 Hz); ¹⁹F NMR (471 MHz, DMSO-d₆) δ: -104.49~-104.55 (m), -232.58 (t, J＝46.6 Hz).

1-(4-Chlorophenyl)-2-fluoroethanone (4c):^[24] 75% yield, yellow solid, m.p. 50~51 ℃ (lit.^[23] m.p. 51~52 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.86 (d, J＝9.0 Hz, 2H), 7.48 (d, J＝8.5 Hz, 2H), 5.52 (d, J_H—F＝47.0 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ: 192.96 (d, J＝15.6 Hz), 141.08, 132.47, 129.83 (d, J＝3.5 Hz), 129.69, 84.72 (d, J_C—F＝183.8 Hz); ¹⁹F NMR (471 MHz, CDCl₃) δ: -229.60.

2-Fluoro-1-(p-tolyl) ethanone (4d):^[22] 69% yield, colorless oil. ¹H NMR (500 MHz, CDCl₃) δ: 7.80 (d, J＝8.0 Hz, 2H), 7.29 (d, J＝8.0 Hz, 2H), 5.55 (d, J_H—F＝47.0 Hz, 2H), 2.42 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ: 193.21 (d, J＝15.2 Hz), 145.30, 131.36, 129.72, 128.08 (d, J＝2.6 Hz), 84.35 (d, J_C—F＝182.3 Hz), 21.89; ¹⁹F NMR (471 MHz, CDCl₃) δ: -230.74.

2-Fluoro-1-(4-(trifluoromethyl)phenyl)ethenone (4e):^[20] 68% yield, colorless solid. m.p. 36~37 ℃ (lit.^[25] m.p. 36~37 ℃); ¹H NMR (500 MHz, DMSO-d₆) δ: 8.09 (d, J＝8.0 Hz, 2H), 7.95 (d, J＝8.5 Hz, 2H), 5.93 (d, J_H—F＝46.0 Hz, 2H); ¹³C NMR (126 MHz, DMSO-d₆) δ: 193.14 (d, J＝14.6 Hz), 136.31, 132.82, 132.56, 128.10 (d, J＝1.9 Hz), 125.47 (m), 122.14, 84.47 (d, J_C—F＝177.2 Hz); ¹⁹F NMR (471 MHz, DMSO-d₆) δ: -61.71, -232.93 (t, J＝45.7 Hz).

1-(4-Cyano)-2-fluoroethanone (4f):^[26] 70% yield, colorless solid. m.p. 103~105 ℃ (lit.^[23] m.p.104~105 ℃); ¹H NMR (500 MHz, DMSO-d₆) δ: 8.04 (s, 4H), 5.91 (d, J_H—F＝46.0 Hz, 2H); ¹³C NMR (126 MHz, DMSO-d₆) δ: 193.50 (d, J＝14.6 Hz), 136.70, 132.87, 128.29, 117.99, 115.79, 84.91 (d, J_C—F＝177.4 Hz); ¹⁹F NMR (471 MHz, DMSO-d₆) δ: -233.00 (t, J＝45.7 Hz).

1-(4-Bromophenyl)-2-fluoroethanone (4g):^[20] 66% yield, colorless solid. m.p. 72~73 ℃ (lit.^[25] m.p. 72~73 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.78 (d, J＝8.0 Hz, 2H), 7.66 (d, J＝8.5 Hz, 2H), 5.52 (d, J_H—F＝47.0 Hz, 2H); ¹³C NMR (126 MHz, CDCl₃) δ: 192.67 (d, J＝16.3 Hz), 132.36, 132.19, 129.38 (d, J＝2.9 Hz), 84.19 (d, J_C—F＝183.8 Hz); ¹⁹F NMR (471 MHz, CDCl₃) δ: -229.65.

2-Fluoro-1-(3-methoxyphenyl)ethanone (4h):^[22] 61% yield, colorless solid. m.p. 52~54 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 7.47~7.46 (m, 2H), 7.39~7.38 (m, 1H), 7.27~7.24 (m, 1H), 5.86 (d, J_H—F＝46.5 Hz, 2H), 3.82 (s, 3H); ¹³C NMR (126 MHz, DMSO-d₆) δ: 194.08 (d, J＝14.4 Hz), 159.83, 135.13, 130.49, 120.30, 112.48, 85.07 (d, J_C—F＝175.8 Hz), 55.75. 19F NMR (471 MHz, DMSO-d₆) δ: -232.72 (t, J＝46.2 Hz).

1-(3-Chlorophenyl)-2-fluoroethan-1-one (4i):^[24] 61% yield, yellow oil. ¹H NMR (500 MHz, DMSO-d₆) δ: 7.91 (t, J＝2.0 Hz, 1H), 7.86~7.84 (m, 1H), 7.76~7.74 (m, 1H), 7.61 (t, J＝8.0 Hz, 1H), 5.89 (d, J_H—F＝46.0 Hz, 2H); ¹³C NMR (126 MHz, DMSO-d₆) δ: 192.52 (d, J＝14.5 Hz), 134.78, 133.32, 133.13, 130.39, 126.83, 125.74, 84.26 (d, J_C—F＝176.5 Hz). 19F NMR (471 MHz, DMSO-d₆) δ:-232.96 (t, J＝47.1 Hz).

2-Fluoro-1-(thiophen-2-yl)ethanone (4j):^[22] 65% yield, colorless solid, m.p. 63~64 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 8.14 (d, J＝4.5 Hz, 1H), 7.97 (dd, J＝3.5Hz, 1Hz, 2H), 7.32~7.30 (m, 1H), 5.75 (d, J_H—F＝46.5 Hz, 2H); ¹³C NMR (126 MHz, DMSO-d₆) δ: 187.67 (d, J＝16.5 Hz), 139.85, 136.07, 134.09 (d, J＝1.9 Hz), 129.45, 84.62 (d, J_C—F＝177.5 Hz); ¹⁹F NMR (471 MHz, DMSO-d₆) δ: -230.75 (t, J＝46.2 Hz).

2-Fluoro-1-(2-methoxyphenyl)ethanone (4k):^[22] 53% yield, colorless solid. m.p. 90~91 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 7.83 (dd, J＝8 Hz, 2 Hz, 1H), 7.65~7.62 (m, 1H), 7.23 (d, J＝8.5 Hz, 1H), 7.12 (t, J＝7 Hz, 1H), 5.54 (d, J_H—F＝48 Hz, 2H), 3.92 (s, 3H); ¹³C NMR (126 MHz, DMSO-d₆) δ: 194.20 (d, J＝14.4 Hz), 159.97, 135.81, 130.16 (d, J＝1.9 Hz), 123.78, 121.31, 113.16, 87.38 (d, J_C—F＝176.5 Hz), 56.47; ¹⁹F NMR (471 MHz, DMSO-d₆) δ: -223.01 (t, J＝52.3 Hz).

2-Fluoro-1-(4-methoxyphenyl)ethanone (4l):^[22] 62% yield, colorless solid. m.p. 81~82 ℃ (lit.^[23] m.p. 78~79 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.90 (t, J＝8.0 Hz, 2H), 6.97 (t, J＝8.5 Hz, 2H), δ: 5.53 (d, J_H—F＝47.0 Hz, 2H) 3.89 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ: 192.38 (d, J＝15.4 Hz), 164.61, 130.65 (d, J＝2.6 Hz), 127.13, 114.50, 84.57 (d, J_C—F＝182.3 Hz), 55.92; ¹⁹F NMR (471 MHz, CDCl₃) δ: -232.50 (t, J＝44.7 Hz). Data matched those previously reported.

Supporting Information Copies of ¹H NMR, ¹³C NMR and ¹⁹F NMR spectra for 2a~2j and 4a~4l. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

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图 1 Representative fluorine-containing drugs

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图式 1 Application of mono(di)-fluoro-1, 3-diketones

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图式 2 Reaction of asymmetric aryl substituted 2, 2-difluoro-1, 3-diaryl-1, 3-diketones

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图式 3 Reaction of asymmetric aryl substituted1, 3-diaryl- 1, 3-diketones

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图式 4 Proposed mechanism for the synthesis of 2a

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图式 5 Proposed mechanism for the synthesis of 4a

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表 1 Optimization of reaction conditions^a


Entry	Solvent	Base	Yield^b/%
1	CH₃CN	Cs₂CO₃	31
2	CH₂Cl₂	Cs₂CO₃	12
3	DMF	Cs₂CO₃	39
4	THF	Cs₂CO₃	51
5	1, 4-Dioxane	Cs₂CO₃	49
6	DMSO	Cs₂CO₃	56
7	DMSO	K₂CO₃	18
8	DMSO	KOH	0
9	DMSO	EtONa	26
10	DMSO	NaOAc	49
11	DMSO	DABCO	13
12	Solvent-free	Cs₂CO₃	82
^a Reaction condition: 1a (0.5 mmol) and base (1.5 mmol) in 2 mL of solvent stirred at room temperature for 10 h; ^b isolated yields.

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表 2 Scope of the 2, 2-difluoro-1, 3-diketones^a


Entry	R	Yield^b/%
1	Ph (1a)	82
2	4-FC₆H₄ (1b)	76
3	4-ClC₆H₄ (1c)	72
4	4-MeC₆H₄ (1d)	50
5	4-CF₃C₆H₄ (1e)	71
6	4-CNC₆H₄ (1f)	68
7	4-BrC₆H₄ (1g)	65
8	3-MeOC₆H₄ (1h)	53
9	3-ClC₆H₄ (1i)	52
10	Thiophene (1j)	60
11	2-MeOC₆H₄ (1k)	Trace
^a Reaction condition: 1 (0.5 mmol), Cs₂CO₃ (1.5 mmol), solvent-free, r.t. for 10 h. ^b isolated yields.

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表 3 Optimization of reaction conditions^a


Entry	Solvent (volume ratio)	t/℃	Base (equiv.)	Yield^b/%
1	CH₃CN/H₂O (20:1)	r.t.	Cs₂CO₃ (3.0)	11
2	CH₃CN	r.t.	Cs₂CO₃ (3.0)	Trace
3	CH₃CN/H₂O (9:1)	r.t.	Cs₂CO₃ (3.0)	25
4	CH₃CN/H₂O (5:1)	r.t.	Cs₂CO₃ (3.0)	20
5	CH₃CN/H₂O (9:1)	40	Cs₂CO₃ (3.0)	29
6	CH₃CN/H₂O (9:1)	60	Cs₂CO₃ (3.0)	43
7	CH₃CN/H₂O (9:1)	Reflux	Cs₂CO₃ (3.0)	53
8	CH₃CN/H₂O (9:1)	Reflux	KOH (3.0)	45
9	CH₃CN/H₂O (9:1)	Reflux	K₂CO₃ (3.0)	43
10	CH₃CN/H₂O (9:1)	Reflux	NaOAc (3.0)	10
11	CH₃CN/H₂O (9:1)	Reflux	Cs₂CO₃ (4.0)	41
12	CH₃CN/H₂O (9:1)	Reflux	Cs₂CO₃ (2.0)	56
13	CH₃CN/H₂O (9:1)	Reflux	Cs₂CO₃ (1.5)	69
14	CH₃CN/H₂O (9:1)	Reflux	Cs₂CO₃ (1.0)	52
^a Reaction condition: The mixture of 3a (0.2 mmol) and Selectfluor^® (0.21 mmol) was stirred with various solvents (2.0 mL) for 2.5 h at different temperature, followed by the addition of various bases. The resulting mixture was continuously stirred for 5 h; ^byields were determined by ¹⁹F NMR using PhCF₃ as an internal standard.

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表 4 Scope of the 1, 3-diaryl-1, 3-diketones^a


Entry	R	Yield^b/%
1	Ph (3a)	68
2	4-FC₆H₄ (3b)	65
3	4-ClC₆H₄ (3c)	75
4	4-MeC₆H₄ (3d)	69
5	4-CF₃C₆H₄ (3e)	68
6	4-CNC₆H₄ (3f)	70
7	4-BrC₆H₄ (3g)	66
8	3-MeOC₆H₄ (3h)	61
9	3-ClC₆H₄ (3i)	61
10	Thiophene (3j)	65
11	2- MeOC₆H₄ (3k)	53
12	4-MeOC₆H₄ (3l)	62
^a Reaction condition: 3 (0.50 mmol), Selectfluor^® (0.53 mmol) was dissolved in 4.0 mL CH₃CN/H₂O (9:1) and refluxed for 2.5 h, after which Cs₂CO₃ (0.75 mmol) was added. The resulting mixture was refluxed for 5 h. ^b isolated yields.

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沈阳化工大学材料科学与工程学院沈阳 110142