Organic Syntheses Procedure

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Org. Synth. 2023, 100, 248-270

DOI: 10.15227/orgsyn.100.0248

Synthesis of 2-Phenyl-4,6-bis(trifluoromethyl)pyridine via NH₄I/Na₂S₂O₄-Mediated Cyclization of Ketoxime Acetates

Submitted by Huawen Huang,*¹ Zhenhua Xu,¹ and Guo-Jun Deng*¹

Checked by Hisahiro Morozumi, Koichi Hagiwara, and Masayuki Inoue

1. Procedure (Note 1)

A. Acetophenone oxime (2). A 100 mL single-necked (15/25) round-bottomed flask equipped with a football-shaped Teflon-coated magnetic stir bar (10 × 25 mm) is charged with hydroxylamine hydrochloride (2.08 g, 29.9 mmol, 1.5 equiv) (Note 2) and anhydrous sodium acetate (3.94 g, 48.0 mmol, 2.3 equiv) (Note 3). Acetophenone (1) (2.40 mL, 20.6 mmol, 1.0 equiv) (Note 4) and anhydrous methanol (40 mL) (Note 5) are added by a plastic syringe to the flask (Figure 1A). The flask is fitted with a water-cooled Dimroth condenser (20 cm, 15/25 joint) (Note 6) and the juncture of the glassware is sealed with Teflon tape. The reaction vessel is placed in a pre-heated silicon oil bath (80 ℃, oil bath temperature) (Note 7) (Figure 1B). The white slurry mixture maintains over the course of the reaction (Notes 8 and 9). After the reaction mixture is stirred open to the air at 80 ℃ for 3 h, the reaction vessel is removed from the oil bath and cooled to 24 ℃ over 30 min (Figure 1C).

Figure 1. A) Reaction mixture after addition of methanol; B) Reaction setup; C) Reaction mixture after 3 h (photos provided by checkers)

Water (60 mL) is added to the flask and the resultant mixture is then transferred to a 200 mL separatory funnel, rinsing the flask with ethyl acetate (3 x 20 mL) (Note 10) (Figure 2A). The two layers are separated, and the aqueous layer is extracted with ethyl acetate (3 x 30 mL). The combined organic layers are dried over anhydrous MgSO₄ (15 g) for 5 min and filtered through a glass funnel with a cotton plug into a 500 mL round-bottomed flask (Figure 2B). The filter cake is rinsed with ethyl acetate (2 x 20 mL) and the filtrate is concentrated with a rotary evaporator under reduced pressure (37 ℃, 15 mmHg) for 15 min. The resulting white liquid is dried under reduced pressure (24 ℃, 4.0 mmHg) for 50 min to afford the crude acetophenone oxime (2) (3.29 g) (Note 11) as a white solid (Figure 2C), which is used in the next step without further purification.

Figure 2. A) The organic layer and the aqueous layer; B) Cotton filtration of MgSO₄ after extraction; C) Crude acetophenone oxime (2) (photos provided by checkers)

B. Acetophenone O-acetyl oxime (3). A 100 mL single-necked (15/25) round-bottomed flask equipped with a football-shaped Teflon-coated magnetic stir bar (10 × 25 mm) is charged with the crude oxime 2 (3.29 g). Acetic anhydride (3.90 mL, 41.3 mmol, 2.0 equiv) is added by a plastic syringe (Note 12) (Figure 3A). The flask is fitted with a water-cooled Dimroth condenser (20 cm, 15/25 joint) and the juncture of the glassware is sealed with Teflon tape. The reaction vessel is placed in a pre-heated silicon oil bath (100 ℃, oil bath temperature) (Notes 13 and 14) (Figure 3B). The color of the solution, which is open to the air, changes to brown after stirring for 3 h at 100 ℃. The reaction vessel is then removed from the oil bath and cooled to 23 ℃ over 30 min (Figure 3C).

Figure 3. A) Reaction mixture after the addition of acetic anhydride; B) Reaction setup; C) Reaction mixture after 3 h (photos provided by checkers)

Ethyl acetate (20 mL) and water (50 mL) are added to the flask and the resultant mixture is then transferred to a 200 mL separatory funnel, rinsing the flask with ethyl acetate (3 x 10 mL) (Figure 4A). The two layers are separated, and the aqueous layer is further extracted with ethyl acetate (2 x 40 mL). The combined organic layers are dried over anhydrous MgSO₄ (10 g) for 5 min and filtered through a glass funnel with a cotton plug into 500 mL round-bottomed flask (Figure 4B). The filter cake is rinsed with ethyl acetate (2 x 20 mL), and the filtrate is concentrated with a rotary evaporator under reduced pressure (46 ℃, 12 mmHg) for 30 min. The resulting brown oil is dried under reduced pressure (23 ℃, 4.0 mmHg) for 1 h to give the crude mixture as a brown solid (Figure 4C).

Figure 4. A) The organic layer and the aqueous layer; B) Cotton filtration of MgSO₄ after extraction; C) Crude brown solid (photos provided by checkers)

The crude residue is recrystallized from hexane/ethyl acetate (5/1) (Figure 5A) to afford acetophenoneO-acetyl oxime (3) (2.51 g, 99.5% purity) as a white solid (Note 15) (Figure 5B). The mother liquor is concentrated by a rotary evaporator under reduced pressure (38 ℃, 18 mmHg) for 10 min to afford the crude residue as a brown oil (Figure 5C). The crude residue is purified by flash column chromatography on silica gel using hexane and ethyl acetate as eluents (Note 16) (Figure 5D) to afford acetophenoneO-acetyl oxime (3) (791 mg, 99.5% purity) as a white solid (Note 17) (Figure 5E). In total, 3.30 g of acetophenoneO-acetyl oxime (3) is obtained (90% yield over two steps from compound 1) (Note 18).

Figure 5. A) Filtration set-up after rinsing with hexane; B) AcetophenoneO-acetyl oxime (3) obtained by recrystallization; C) Concentrated mother liquor; D) Purification by column chromatography; E) AcetophenoneO-acetyl oxime (3) obtained by column chromatography (photos provided by checkers)

C. 2-Phenyl-4,6-bis(trifluoromethyl)pyridine (5). AcetophenoneO-acetyl oxime (3) (2.12 g, 12.0 mmol, 1.0 equiv) in a 100 mL single-necked (15/25) round-bottomed flask is mixed with toluene (10 mL), which is removed by rotary evaporation under reduced pressure (40 ℃, 16 mmHg) for 10 min. This process is repeated two more times with toluene (2 × 10 mL). An oven-dried football-shaped Teflon-coated magnetic stir bar (10 × 25 mm), NH₄I (1.74 g, 12.0 mmol, 1.0 equiv) (Note 19), Na₂S₂O₄ (2.46 g, 12.0 mmol, 1.0 equiv) (Note 20), and powdered molecular sieves 4A (1.06 g) (Note 21) are successively added to the flask. Then, hexafluoroacetylacetone (4) (3.40 mL, 24.3 mmol, 2.0 equiv) (Note 22) and anhydrous toluene (40.0 mL) (Note 23) are added by a plastic syringe (Figure 6A). The flask is capped with a 15/25 three-way stopper with joint Teflon plug, which is connected to a Schlenk line. The juncture of the glassware is sealed with Teflon tape and the stopper is fixed with rubber bands. The flask is evacuated and backfilled with argon three times (Note 24) (Figure 6B). Then, the flask is sealed and disconnected from the Schlenk line. The resulting red solution is placed behind a blast shield and then onto a pre-heated silicon oil bath (130 ℃, oil bath temperature) (Notes 25 and 26) (Figure 6C). After the reaction mixture is stirred for 10 h in the oil bath, the reaction vessel is removed from the oil bath and allowed to cool to 24 ℃ (Note 27) (Figure 6D).

Figure 6. A) Reaction mixture after the addition of toluene; B) Set-up for substituting air with argon in the flask C) Reaction setup; D) Reaction mixture after 10 h (photos provided by checkers)

The resulting solution is filtered through a short pad of silica gel (Note 28) (Figure 7A) and eluted with ethyl acetate (200 mL) into 500 mL round-bottomed flask. The resulting solution is concentrated by a rotary evaporator under reduced pressure (37 ℃, 26 mmHg) for 5 min to afford the crude mixture as a red oil (Figure 7B). The crude residue is purified by flash column chromatography on silica gel using hexane and ethyl acetate as eluents (Note 29) (Figure 7C) to afford 2-phenyl-4,6-bis(trifluoromethyl)pyridine (5) as a light brown oil (2.41 g, 8.40 mmol, 69% yield, 97.7 % purity) (Notes 30, 31, and 32) (Figure 7D).

Figure 7. A) Filtration through a short pad of silica gel; B) Crude red oil; C) Purification by column chromatography; D) 2-Phenyl-4,6-bis(trifluoromethyl)pyridine (5) after column chromatography (photos provided by checkers)

2. Notes

1. Prior to performing each reaction, a thorough hazard analysis and risk assessment should be carried out with regard to each chemical substance and experimental operation on the scale planned and in the context of the laboratory where the procedures will be carried out. Guidelines for carrying out risk assessments and for analyzing the hazards associated with chemicals can be found in references such as Chapter 4 of "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011; the full text can be accessed free of charge at https://www.nap.edu/catalog/12654/prudentpractices-in-the-laboratory-handling-and-management-of-chemical. See also "Identifying and Evaluating Hazards in Research Laboratories" (American Chemical Society, 2015) which is available via the associated website "Hazard Assessment in Research Laboratories" at https://www.acs.org/content/acs/en/about/governance/committees/chemicalsafety/hazard-assessment.html. In the case of this procedure, the risk assessment should include (but not necessarily be limited to) an evaluation of the potential hazards associated with acetophenone, hydroxylamine hydrochloride, anhydrous sodium acetate, methanol, ethyl acetate, acetic anhydride, hexane, toluene, ammonium iodide, sodium dithionite, hexafluoroacetylacetone, and molecular sieves 4A.

2. The submitters purchased hydroxylamine hydrochloride (98.5%) from Hunan Huihong Chemical Reagent Company Limited and used it as received. Hydroxylamine hydrochloride (99%) was purchased from Sigma-Aldrich and used as received (checkers).

3. The submitters purchased anhydrous sodium acetate (99%) from Aladdin Chemical Reagent Company Limited and used the material as received. Anhydrous sodium acetate (99%) was purchased from Thermo Fisher Scientific Co., Inc. and used as received (checkers).

4. The submitters purchased acetophenone (99%) from Energy Chemical and used the material as received. Acetophenone (99%) was purchased from Kanto Chemical Co., Inc. and used as received (checkers).

5. The submitters purchased anhydrous methanol from Tianjin Fuyu Chemical Reagent Company Limited and used the material as received. Anhydrous methanol (≥99.8%) was purchased from FUJIFILM Wako Pure Chemical Corporation and used as received (checkers).

6. Condenser (C629300) was purchased from Synthware (submitters). Dimroth condenser (No. 1220030) was purchased from Yazawa-Kagaku Co., Inc (checkers).

7. A 500 mL oil bath was used with a stir rate of ~ 500 rpm (submitters). A 650 mL oil bath was used with a stir rate of 800 rpm (checkers).

8. A milky color solution was observed with no color change over the course of the reaction.

9. The reaction was monitored by TLC analysis on silica using hexane/ethyl acetate (10/1, v/v) (Figure 8). R_f of 1 = 0.39, R_f of 2 = 0.30.

Figure 8. Thin-layer chromatography (TLC) analysis of the reaction mixture; A) Visualized by 254 nm UV. Left-to-right: Compound 1; Co-spot of compound 1 and the reaction mixture; The reaction mixture; (B) Visualized by anisaldehyde stain. Left-to-right: Compound 1; Co-spot of compound 1 and the reaction mixture; The reaction mixture (photos provided by checkers)

10. Ethyl acetate (>99.0%) was purchased from Kanto Chemical Co., Inc. and used as received.

11. Characterization data of the non-purified acetophenone oxime (2): white solid. mp 53-55 ℃. ¹H NMR pdf (400 MHz, CDCl₃) δ: 7.64-7.62 (m, 2H), 7.39-7.37 (m, 3H), 2.30 (s, 3H). ¹³C NMR pdf (100 MHz, CDCl₃) δ: 156.0, 136.4, 129.3, 128.5, 126.0, 12.4. HRMS (ESI^-) m/z calcd. for C₈H₈NO [M-H]^-134.0611; found 134.0608. A reaction on half-scale provided 1.68 g of the unpurified product.

12. The submitters purchased acetic anhydride (98.5%) from Chengdu Kelon Chemical Reagent Factory and used the material as received. Acetic anhydride (>99.0%) was purchased by the checkers from Tokyo Chemical Industry Co., Ltd. and used as received.

13. A 650 mL oil bath was used with a stir rate of 800 rpm. The submitters noted that a light yellow solution was obtained, and no color change was observed over the course of the reaction.

14. The checkers monitored the reaction by TLC analysis on silica using hexane/ethyl acetate (5/1, v/v) (Figure 9). R_f of 2 = 0.40, R_f of 3 = 0.29.

Figure 9. Thin-layer chromatography (TLC) analysis of the reaction mixture; A) Visualized by 254 nm UV. Left-to-right: crude 2; Co-spot of crude 2 and the reaction mixture; The reaction mixture; (B) Visualized by anisaldehyde stain. Left-to-right: crude 2; crude 2 and the reaction mixture; reaction mixture (photos provided by checkers)

15. The checkers performed recrystallization of the crude oxime acetate as follows. Ethyl acetate (2 mL) and hexane (10 mL) are added to the crude residue at 23 ℃ and the solid is dissolved at 38 ℃. The solution is cooled to 23 ℃ for 8 min and then placed in an ice bath for 2 h to induce the formation of white solid. The solid is vacuum filtered through a Kiriyama-funnel (S-60, fiter paper: No.5B, 60 mmΦ, washed with ice-cooled hexane (15 mL ×2), and dried under reduced pressure (23 ℃, 4.7 mmHg) for 1 h. 2.51 g of acetophenoneO-acetyl oxime (3) is obtained. The purity of compound 3 was determined to be 99.5% by quantitative ¹H NMR spectroscopy in CDCl₃ using 15.3 mg of the compound 3 and 15.4 mg of dibromomethane (Nacalai Tesque, Inc., >99.0%) as an internal standard.

16. Sand was purchased from Nacalai Tesque, Inc. and used as received. Silica gel (Silica gel 60 N, 0.040-0.050 mm, spherical and neutral) was purchased from Kanto Chemical Co., Inc. and used as received. Hexane (>96.0%) was purchased from Kanto Chemical Co., Inc. and used as received. Toluene (99%) was purchased from FUJIFILM Wako Pure Chemical Corporation and used as received (checkers). Column chromatography was performed as follows. Flash column (4.8 cm diameter) is charged with sea sand to a height of 2 cm and then with silica gel (120 g) using a wet-pack method to give a column of 15 cm height. Sea sand with a 1 cm height is added to the top of the column. The crude oil is loaded onto the column using 15 mL of toluene. Fraction collection (100 mL) is then started using test tubes. Elution is continued with 500 mL of hexane/ethyl acetate (20/1, v/v), 500 mL of hexane/ethyl acetate (15/1, v/v), 1500 mL of hexane/ethyl acetate (10/1, v/v), and then 1500 mL of hexane/ethyl acetate (6/1, v/v) using compressed air. As illustrated in Figure 10, the fractions containing the acetophenoneO-acetyl oxime (3) are identified as fractions No. 18 through No. 24 by TLC (R_f of 0.23, hexane/ethyl acetate = 5/1 (v/v), visualized by 254 nm UV). These fractions are combined, concentrated using a rotary evaporator under reduced pressure (37 ℃, 26 mmHg) for 20 min, and then placed under reduced pressure (23 ℃, 6.8 mmHg) for 2 hours to remove residual solvent. Compound 3 (791 mg) is obtained.

Figure 10. TLC analysis of column chromatography visualized by 254 nm UV (photo provided by checkers)

17. Characterization data of acetophenoneO-acetyl oxime (3): white solid, mp 54-56 ℃. ¹H NMR pdf (400 MHz, CDCl₃) δ: 7.75-7.73 (m, 2H), 7.47-7.39 (m, 3H), 2.40 (s, 3H), 2.28 (s, 3H). ¹³C NMR pdf (100 MHz, CDCl₃) δ: 168.9, 162.4, 134.8, 130.5, 128.5, 126.9, 19.8, 14.4. IR (KBr film): 3057, 1761, 1616, 1444, 1362, 1310, 1208, 896, 773, 695 cm⁻¹. HRMS (ESI+) m/z calcd. for C₁₀H₁₁NO₂Na [M+Na]⁺ 200.0682; found 200.0685. The purity of the acetophenoneO-acetyl oxime (3) was determined to be 99.5% by quantitative ¹H NMR pdf spectroscopy in CDCl₃ using 14.6 mg of the compound 3 and 15.2 mg of dibromomethane (Nacalai Tesque, Inc., >99.0%) as an internal standard.

18. When the two-step reaction sequence was carried out with 10.3 mmol of acetophenone (1), acetophenoneO-acetyl oxime (3) was obtained (1.72 g, 94% yield over 2 steps from compound 1, 98.7% purity).

19. The submitters purchased ammonium iodide (99%) from Bide Pharmatech Ltd, Ih was used as received. Ammonium iodide (≥99.5%) was purchased from FUJIFILM Wako Pure Chemical Corporation and dried under reduced pressure (4.6 mmHg) for 8 h before use (checkers).

20. The submitters purchased sodium dithionite (90%) from Aladdin Chemical Reagent Company Limited, Ih was used as received. Sodium dithionite (>85.0%) was purchased from Tokyo Chemical Industry Co., Ltd. and dried under reduced pressure (4.6 mmHg) for 8 h before use (checkers).

21. Powdered molecular sieves 4A were purchased from Sigma-Aldrich and dried by heating with a heat gun under reduced pressure (4.8 mmHg) for 3 min before use. The checkers found that molecular sieves 4A prevented the hydrolysis of 3 into acetophenone (1) under the reaction conditions.

22. The submitters purchased hexafluoroacetylacetone (98%) from Energy Chemical Reagent Company LIed, which was used as received. Hexafluoroacetylacetone (>95.0%) was purchased from Tokyo Chemical Industry Co., Ltd. and dried with molecular sieves 4A (beads) purchased from Sigma-Aldrich (checkers).

23. The submitters purchased toluene from Tianjin Fuyu Chemical Reagent Company Limited and used the solvent as received. Anhydrous toluene (99.5%) was purchased from FUJIFILM Wako Pure Chemical Corporation and used as received (checkers).

24. The flask, fitted with a three-way stopper, was evacuated by vacuum pump until bubbling of the solution mixture was observed, at which time the flask was backfilled with argon. This process was repeated three times.

25. A 1200 mL oil bath was used with a stir rate of 800 rpm. A light brown solution was quickly formed, after which no color change was observed over the course of the reaction.

26. Because the flask is sealed and then heated, a blast shield should be used to shield the surroundings while heating the reaction mixture.

27. The checkers monitored the reaction by TLC analysis on silica using hexane/ethyl acetate (5/1, v/v) (Figure 11). R_f of 3 = 0.30, R_f of 5 = 0.75.

Figure 11. Thin-layer chromatography (TLC) analysis of the reaction mixture visualized by 254 nm UV. Left-to-right: compound 3; co-spot of compound 3 and the reaction mixture; reaction mixture (photo provided by checkers)

28. Silica gel (Silica gel 60 N, 0.100-0.210 mm, spherical and neutral) was purchased from Kanto Chemical Co., Inc. and used as received.

29. Column chromatography was performed as follows. A flash column (5.2 cm diameter) is charged with sea sand to a height of 2 cm and then with silica gel (Silica gel 60 N, 0.040-0.050 mm, spherical and neutral, 100 g) using a wet-pack method to give a column of 11 cm height. Sea sand with a 2 cm height is added to the top of the column. The crude oil is loaded onto the column using 50 mL of hexane. Fraction collection (100 mL) is then started using test tubes. Elution is continued with 800 mL of hexane and then 1700 mL of hexane/ethyl acetate (100/1, v/v) using compressed air. As illustrated in Figure 12, the fractions containing the 2-phenyl-4,6-bis(trifluoromethyl)pyridine (5) are identified as fractions No. 7 through No. 22 by TLC (R_f of 0.75, hexane/ethyl acetate = 5/1 (v/v), visualized by 254 nm UV). These fractions are combined, concentrated using a rotary evaporator under reduced pressure (37 ℃, 26 mmHg) for 5 min, and then placed under reduced pressure (23 ℃, 6.5 mmHg) for 20 min to remove residual solvent. Compound 5 (2.41 g) is obtained.

Figure 12. TLC analysis of column chromatography visualized by 254 nm UV (photo provided by checkers)

30. Characterization data of 2-phenyl-4,6-bis(trifluoromethyl)pyridine (5): light brown oil. ¹H NMR pdf (400 MHz, CDCl₃) δ: 8.13-8.10 (m, 3H), 7.80 (s, 1H), 7.56-7.52 (m, 3H). ¹³C NMR pdf (100 MHz, CDCl₃) δ: 159.4, 149.5 (q, J_C-F = 35.9 Hz), 140.8 (q, J_C-F = 34.5 Hz), 136.3, 130.7, 129.1, 127.2, 122.4 (q, J_C-F = 275.0 Hz), 121.0 (q, J_C-F = 275.9 Hz), 118.4, 114.3. IR (KBr film): 3072, 1620, 1588, 1462, 1389, 1280, 1199, 1145, 892, 688 cm⁻¹. HRMS (APCI+) m/z calcd. for C₁₃H₈F₆N [M+H]⁺ 292.0555; found 292.0556.

31. The purity of the 2-phenyl-4,6-bis(trifluoromethyl)pyridine (5) was determined to be 97.7% by quantitative ¹H NMR pdf spectroscopy in CDCl₃ using 19.7 mg of the product 5 and 11.6 mg of dibromomethane (Nacalai Tesque, Inc., >99.0%) as an internal standard (checkers).

32. When the reaction was carried out with 5.98 mmol of acetophenoneO-acetyl oxime (3), 1.27 g of 2-phenyl-4,6-bis(trifluoromethyl)pyridine (5) was obtained (73% yield, 97.6% purity).

Working with Hazardous Chemicals

The procedures in Organic Syntheses are intended for use only by persons with proper 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; the full text can be accessed free of charge at http://www.nap.edu/catalog.php?record_id=12654). 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.

In some articles in Organic Syntheses, chemical-specific hazards are highlighted in red "Caution Notes" within a procedure. It is important to recognize that the absence of a caution note does not imply that no significant hazards are associated with the chemicals involved in that procedure. Prior to performing a reaction, a thorough risk assessment should be carried out that includes a review of the potential hazards associated with each chemical and experimental operation on the scale that is planned for the procedure. Guidelines for carrying out a risk assessment and for analyzing the hazards associated with chemicals can be found in Chapter 4 of Prudent Practices.

The procedures described in Organic Syntheses are provided as published and are 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

In recent decades, synthetic organofluorine chemistry has attracted intensive attention due to the successful introduction of fluorine for the development of small-molecule drugs.^2,3 Generally, fluorine functionalities are introduced to increase the basicity or to enhance the metabolic stability and binding affinity of a given molecule, which thereby results in improved bioactivity.⁴ The pyridine skeleton, well-recognized as an important N-heterocyclic structural unit, exists in numerous naturally occurring compounds, drugs, reagents for organocatalysis, ligands and functional materials.⁵ Consequently, a series of efficient methods for synthesizing polysubstituted pyridines have been developed.⁶ Despite these applications, few methods are reported for the introduction of a trifluoromethyl (-CF₃) group onto pyridine rings.⁷ Within our program on the method development for the synthesis of pyridines and other N-heterocycles,⁸ we are interested in the development of methodology for the construction of trifluoromethylated pyridines from readily available starting materials.

O-Acyl oximes have been used as versatile building blocks to form N-containing heterocycles through catalytic N-O bond reduction by transition-metal-mediated oxidative addition.¹⁰ In this work, we have developed a NH₄I/Na₂S₂O₄-based reductive system which enables the N−O bond cleavage of oximes and thereby promotes the assembly of pharmacologically significant fluorinated pyridines. Hence, this protocol provides a modular access to 4,6-bis(trifluoromethyl)pyridines by the reductive cyclization of O-acyl oximes and hexafluoroacetylacetone (Table 1).¹¹ Salient features of this method include easily available starting materials, broad functional group compatibility, good yields, and high regio- and chemo-selectivity.

Table 1. NH₄I/Na₂S₂O₄-mediated reductive formation of 4,6-bis(trifluoromethyl)pyridines

References and Notes

Key Laboratory for Green Organic Synthesis and Application of Hunan Province, Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China. E-mail: hwhuang@xtu.edu.cn; gjdeng@xtu.edu.cn. We thank the National Natural Science Foundation of China (21602187, 22071211), Hunan Provincial Natural Science Foundation of China (2020JJ3032), and the Hunan Provincial Innovative Foundation of Postgraduate (CX20190482, XDCX2019B091) for financial support of this work.
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Appendix
Chemical Abstracts Nomenclature (Registry Number)

Acetophenone; (1) (98-86-2)

Hydroxylamine hydrochloride; (5470-11-1)

Anhydrous sodium acetate: Sodium acetate; (127-09-3)

Acetic anhydride; (108-24-7)

Ammonium iodide; (12027-06-4)

Sodium dithionite; (7775-14-6)

Molecular sieves 4A; (70955-01-0)

	Hauwen Huang received his B.S. degree from Northwest University in 2009 and his Ph.D. degree under the guidance of Prof. Huanfeng Jiang from South China University of Technology in 2014. In the same year, he joined into Xiangtan University. In 2016-2018, he was supported by the China Scholarship Council and went to the University of Goettingen as a postdoctoral fellow under the guidance of Prof. Lutz Ackermann. He was appointed as a full professor in the College of Chemistry at Xiangtan University in 2021. His current research is focusing on the development and application of novel and environmentally friendly organic synthesis.
	Zhenhua Xu was born in Henan, China. He graduated from Huanghuai College in 2016 with a B.S. degree, and received his Ph.D. degree in Chemistry in 2022 under the cooperative supervision of Prof. Huawen Huang and Prof. Guo-Jun Deng from Xiangtan University. He was appointed as an assistant professor in the School of Chemistry and Chemical Engineering at Suzhou University in 2022. He is currently working on the development of novel and sustainable methods for the synthesis of functionalized nitrogen-containing heterocycles from easily accessible raw materials.
	Guo-Jun Deng received his B.S. degree from Xiangtan University and completed his Ph.D. degree in 2004 in chemistry from the Institute of Chemistry, Chinese Academy of Sciences with Prof. Qinhua Fan. He conducted post-doctoral studies with Prof. Lukas J. Goossen at Max Planck Institute, with Prof. E. Schoffers at Western Michigan University and with Prof. Chao-Jun Li at Tulane University and McGill University. In 2009, he joined the College of Chemistry at Xiangtan University as a full professor. His research interests lie in the development of environmentally benign methodologies for C-C and C-hetero bond formation.
	Hisahiro Morozumi was born in Chiba, Japan. He graduated from the University of Tokyo in 2022 with B.Sc. in Pharmaceutical Sciences. He is continuing his graduate studies at the University of Tokyo under the supervision of Prof. Masayuki Inoue. His research interests are in the area of the total synthesis of complex natural products.
	Koichi Hagiwara was born in Kanagawa, Japan., in 1989. He received his B.Sc. degree in 2013 from the University of Tokyo, and his Ph.D. degree in Pharmaceutical Sciences in 2019 under the supervision of Prof. Masayuki Inoue. He was appointed as an assistant professor in the Graduate School of Pharmaceutical Sciences at the University of Tokyo in 2017. His research interests include the total synthesis of bioactive and highly complex natural products.

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