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• 

  1    Introduction

  The trifluoromethylation of organic molecules is of significant importance in the field of pharmaceuticals, agrochemicals, and advanced materials^[1] owing to the incorporation of CF₃ moiety into compounds resulted in enhanced properties such as lipophilicity, metabolic stability, bioavailability, and binding selectivity.^[2] Among which, for example, Panomifene^[3] exhibits antie-strogenic and tumorinhibiting activities superior to those of tamoxifen when used for the clinical treatment of breast cancer. Therefore a variety of methods have been reported to form C-CF₃ bonds, ^[4]including forming C-CF₃ bonds on C=O, ^[5] C=N, ^[6] or C=C, ^{[7, 8]}with cross-coupling the trifluoromethyl reagents and prefunctionalized aromatics, ^[9] or other methods.^[10] The trifluoromethylated olefins are generally derived from the reaction of prefunctionalized olefins with trifluoromethylating reagents, ^[11] as well as adding trifluoromethylating reagents to terminal alkynes, ^[12]or from other indirect routes.^[13]Owing to its low reactivity, direct olefinic C-H trifluoromethylation still remains as an interesting topic and a few methods were developed up to now by transition-metal-catalyzed^[14] and metal free^[15]means, wherein quinones, ^{[16a, 16b]} uracil, ^[16c] and terminal olefins^[16d~16h]were utilized as starting materials.^{[17, 18]}Hence, introducing new protocols for trifluoromethylation of olefinic C-H bonds are still demanded and continue to draw the attention of the synthetic community.

  Literatures were documented that α-oxoketene dithioacetals, strongly electron-donating moieties and easily cleaved, possess unique features when serving as versatile reagents^[19] in the synthesis of heterocycles^[20] and aromatic compounds, ^[21] as well as odorless thiol equivalent compounds.^[22] Therefore its preparation and transformation has attracted particular interests from the realm of organic synthesis and among which the trifluoromethylation reaction has been realized by metal-free or Cu^Ⅱ-catalyzed conditions.^{[7, 8, 23]}

  Recently, visible-light-mediated radical functionali-zation of olefins to introduce the trifluoromethyl group has been shown to be a feasible and efficient method.^{[16g, 16h]}Yet trifluoromethylation of the internal olefin remains an elusive goal. As α-oxoketene dithioacetals are polar functionalized alkenes, we therefore envisioned that internal olefins can be tuned to become highly polarized by attaching to such strongly electron-donating group, and those modified internal olefins can be utilized as backbones to prepare multi-substituted trifluoromethylated olefins under photocatalytic conditions. Herein, we report a conceptually new approach to the trifluoromethylation of α-oxoketene dithioacetals via visible light photoredox catalysis (Scheme 1).

  

  Figure Scheme 1. Trifluoromethylation of internal olefinic C-H bonds

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  2    Results and Discussion

  We commenced our investigation with α-oxoketene dithioacetal 1a as a model substrate. Treating 1a with Togni's reagent 4a, fac-[Ir (ppy)₃] and K₂CO₃in DMSO, the trifluoromethylated α-oxoketene dithioacetal was obtained in good yield within 39 h under 5 W Blue LEDs at room temperature (Table 1, Entry 1). With the promising initial result, we continued to optimize the reaction conditions. First, different photocatalysts were evaluated (Table 1, Entries 3 and 4). We were pleased to find that Ru (bpy)₃Cl₂was more effective to the reaction. Next, we examined the effect of other parameters on the reaction, including solvent, base, the stoichiometry of Togni's reagent and atmosphere (Table 1, Entries 5~18). In addition, control experiment showed that the visible light was required for the transformation (Table 1, Entry 2).

  Table1. Screening of reaction conditions^a

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  Entry	PC (mol%)	Base	4a/equiv.	Solvent	Yieldb/%
  1	5a(5.0)	Na2CO3	3	DMSO	70c
  2	5a(5.0)	Na2CO3	3	DMSO	0d
  3	5b(5.0)	Na2CO3	3	DMSO	78
  4	5c(5.0)	Na2CO3	3	DMSO	87c, 92
  5	5c(5.0)	Na2CO3	3	DMSO	58e
  6	5c(5.0)	Na2CO3	2	DMSO	91
  7	5c (5.0)	Na2CO3	1.5	DMSO	87c, 92
  8	5c(5.0)	Na2CO3	1.5	CH3OH	58
  9	5c(5.0)	Na2CO3	1.5	DMF	62
  10	5c(5.0)	Na2CO3	1.5	CH2Cl2	41
  11	5c(5.0)	Na2CO3	1.5	CH3CN	trace
  12	5c(5.0)	Na2CO3	1.5	toluene	49
  13	5c(5.0)	-	1.5	DMSO	90
  14	5c(5.0)	KH2PO4	1.5	DMSO	72
  15	5c(5.0)	KF	1.5	DMSO	90
  16	5c(5.0)	DBU	1.5	DMSO	76
  17	5c(1.0)	Na2CO3	1.5	DMSO	70
  18	5c(2.0)	Na2CO3	1.5	DMSO	81
  aConditions: 1a (0.1 mmol), N2 atmosphere. bThe yield was determined by gas chromatography. cIsolated Yield.dNo light.eUnder air.

  Table1. Screening of reaction conditions^a

  With the optimized conditions in hand, a variety of α-oxoketene dithioacetals were prepared and then sub-jected to the reaction conditions. The results were listed in Scheme 2. Substrates bearing different groups, including methoxy, chloro, bromo, and fluoro groups at para, orthoor meta position of aromatic ring, were tolerant on the reaction conditions to provide corresponding products (Scheme 2, 2a~2n). When the aromatic ring connecting to carbonyl group was changed to methyl, the substrate was still suitable for the reaction, giving the desired ketene dithioacetals 2oin 58% yield. By changing the dithioalkyl moiety to -S (CH₂)₃S-, we noticed that the corresponding substrate exhibited lower reactivity to form the target product 2s(40%). And to our surprise, the acyclic dimethylthio analogue of 1 reacted smoothly with Togni's reagent to afford product 2r in 90% yield.

  

  Figure Scheme 2. Trifluoromethylation of α-oxoketene dithioacetals^{a, b}

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  On comparison with previous documents, ^{[8, 23]} visible-light photoredox catalytic reactions showed more extensive substrate scope, better efficiency and mild reaction condition. Moreover, the trifluoromethylation of 2-thienoyl and furoyl substrates could undergo successfully to afford both mono-and di-trifluoromethylation products (Scheme 2, 2p, 2p', and 2q, 2q') under standard conditions. Based on that, we anticipated controlling the scale of Togni's reagent should produce different ratios of mono-and di-trifluoromethylation products. As showed in Table 2, when the Togni's reagent increased to 3 equiv., the di-trifluoromethylation products could be obtained as the single or major products (Table 2, Entries 3 and 6).

  Table2. mono-and di-trifluoromethylation of the heterocyclic substrates^{a, b}

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  Entry	R	Togni’ reagent/equiv.	2Yieldb/%	2'Yieldb/%
  1	O	1.0	43	13
  2	O	1.5	27	29
  3	O	3.0	0	72
  4	S	1.0	75	10
  5	S	1.5	58	29
  6	S	3.0	40	44
  aConditions: 1 (0.1 mmol), Ru (bpy)3Cl2 (5% mmol), Na2CO3 (3 mmol), in DMSO, N2atmosphere. bIsolated yield.

  Table2. mono-and di-trifluoromethylation of the heterocyclic substrates^{a, b}

  In addition, the scope was extended to the bromination reaction by changing the Togni's reagent to CBr₄. The reaction proceeded smoothly and the brominated α-oxoketene dithioacetals was obtained in 79% isolated yield (Scheme 3).

  

  Figure Scheme 3. Bromination of1a

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  A plausible reaction pathway for the trifluoromethylation of α-oxoketene dithioacetals was proposed as shown in Scheme 4. Once activated by visible light, Ru (bpy)₃²⁺ reached to the excited state Ru (bpy)₃²⁺* which then would readily be oxidized by Togni's reagent 4ato produce Ru (bpy)₃³⁺, while CF₃radical was released simultaneously. In succession, addition of CF₃ radical to substrate 1delivered the trifluoromethylated secondary carbon radical intermediate A. Afterwards, the single-electron oxidation of Aoccurred to form the carbon center cation intermediate B, which then produce the desired product 2 by deprotonation.

  

  Figure Scheme 4. Proposed possible mechanism for the trifluoromethylation of α-oxoketene dithioacetals

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  During our investigation, to test the potential application of this protocol, a gram-scale reaction of 1a was carried out under standard reaction conditions and the desired product was obtained in 82% yield (Eq. 1).

  3    Conclusion

  In conclusion, we have developed a visible-light-induced trifluoromethylation of α-oxoketene dithioacetals under mild conditions. This approach features not only in exhibiting high efficiency but also in expanding the substrate scope that is difficult to access with known methods.

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• 

  Scheme 1  Trifluoromethylation of internal olefinic C-H bonds

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  Scheme 2  Trifluoromethylation of α-oxoketene dithioacetals^{a, b}

  ^aConditions: 1 (0.1 mmol), Togni’s reagent (0.15 mmol), Ru (bpy)₃Cl₂(5% mmol), Na₂CO₃ (3 mmol), in DMSO, N₂ atmosphere. ^bIsolated yield.

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  Scheme 3  Bromination of1a

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  Scheme 4  Proposed possible mechanism for the trifluoromethylation of α-oxoketene dithioacetals

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  Table 1.  Screening of reaction conditions^a

  Entry	PC (mol%)	Base	4a/equiv.	Solvent	Yieldb/%
  1	5a(5.0)	Na2CO3	3	DMSO	70c
  2	5a(5.0)	Na2CO3	3	DMSO	0d
  3	5b(5.0)	Na2CO3	3	DMSO	78
  4	5c(5.0)	Na2CO3	3	DMSO	87c, 92
  5	5c(5.0)	Na2CO3	3	DMSO	58e
  6	5c(5.0)	Na2CO3	2	DMSO	91
  7	5c (5.0)	Na2CO3	1.5	DMSO	87c, 92
  8	5c(5.0)	Na2CO3	1.5	CH3OH	58
  9	5c(5.0)	Na2CO3	1.5	DMF	62
  10	5c(5.0)	Na2CO3	1.5	CH2Cl2	41
  11	5c(5.0)	Na2CO3	1.5	CH3CN	trace
  12	5c(5.0)	Na2CO3	1.5	toluene	49
  13	5c(5.0)	-	1.5	DMSO	90
  14	5c(5.0)	KH2PO4	1.5	DMSO	72
  15	5c(5.0)	KF	1.5	DMSO	90
  16	5c(5.0)	DBU	1.5	DMSO	76
  17	5c(1.0)	Na2CO3	1.5	DMSO	70
  18	5c(2.0)	Na2CO3	1.5	DMSO	81
  aConditions: 1a (0.1 mmol), N2 atmosphere. bThe yield was determined by gas chromatography. cIsolated Yield.dNo light.eUnder air.

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  Table 2.  mono-and di-trifluoromethylation of the heterocyclic substrates^{a, b}

  Entry	R	Togni’ reagent/equiv.	2Yieldb/%	2'Yieldb/%
  1	O	1.0	43	13
  2	O	1.5	27	29
  3	O	3.0	0	72
  4	S	1.0	75	10
  5	S	1.5	58	29
  6	S	3.0	40	44
  aConditions: 1 (0.1 mmol), Ru (bpy)3Cl2 (5% mmol), Na2CO3 (3 mmol), in DMSO, N2atmosphere. bIsolated yield.

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•