Organic Syntheses Procedure

^
Top

Org. Synth. 2023, 100, 136-158

DOI: 10.15227/orgsyn.100.0136

α-Oxamination of Amides via Electrophilic Activation

Submitted by Miran Lemmerer,⁺¹ Ján Matyašovský,⁺¹ Roberto Tinelli¹ and Nuno Maulide*¹

Checked by Colin Knus, Jaime Martín, Jorge A. González, and Cristina Nevado

1. Procedure (Note 1)

A. 1-(Pyrrolidin-1-yl)undec-10-en-1-one (1). An oven-dried (at 150 °C) 250 mL one-necked, round-bottomed flask, equipped with an egg-shaped, PTFE-coated magnetic stir bar (3 cm), is charged with pyrrolidine (Note 2) (7.11 g, 100 mmol, 1.0 equiv) and Et₃N (Note 3) (21.0 mL, 150 mmol, 1.50 equiv) (Figure 1A). Anhydrous dichloromethane (Note 4) (100 mL) is added, the flask is sealed with a rubber septum (fitted with a 0.8 mm ⌀ needle) and then cooled to between 0 and 5 °C in a water-ice bath. While stirring (>800 rpm), 10-undecenoyl chloride (Notes 5 and 6) (23.6 mL, 110 mmol, 1.10 equiv) is added dropwise (50 mL syringe fitted with a 0.8 mm ⌀ needle) over the course of 15 min. The cooling bath is removed (Figure 1B), and the reaction mixture is allowed to warm to room temperature (23 °C) and stirred at this temperature for 16 h.

Figure 1. Reaction setup: A) After addition of pyrrolidine; B) After removal of cooling bath (photos provided by submitters)

After this time, the mixture is diluted with Et₂O (Note 7) (200 mL) and the organic phase is washed sequentially with 1 M HCl (Note 8) (50 mL), saturated aqueous NaHCO₃ (Note 9) (50 mL) and brine (Note 10) (50 mL). The washed organic layer is dried over anhydrous MgSO₄ (Note 11) (5 g) and filtered via gravitational filtration using a glass funnel equipped with filter paper (Note 12). The filtrate is concentrated by rotary evaporation (450 mmHg at 40 °C, followed by 7.5 mmHg at 40 °C), affording a thick yellow oil. The oil is mixed with heptane (Note 13) (5 mL) and loaded onto a silica gel column (300 ± 10 g; column dimensions: 6 x 30 cm, equilibrated with heptane) (Note 14), and 80 mL fractions are collected (Figure 2A). The column is initially eluted with 1 L of a 30% EtOAc (Note 15) in heptane mixture, which is switched to 100% EtOAc once the compound of interest starts to elute (Figure 2B). The compound of interest is collected in fractions 13-34, the solvent is removed by rotary evaporation (120 mmHg mbar at 40 °C, and 0.8 mmHg at 40 °C, followed by high vacuum (ca. 0.05 mmHg) at room temperature (23 °C) for 6 h) to obtain the product 1 as a colorless oil (22.2 g, 94%) (Figure 2C) (Notes 16 and 17).

Figure 2. A) Chromatography setup; B) TLC analysis of collected fractions; C) Product in a 100 mL flask (photos provided by submitters)

B. 1-(Pyrrolidin-1-yl)-2-((2,2,6,6-tetramethylpiperidin-1-yl)oxy) undec-10-en-1-one (2). An oven-dried (at 150 °C) 1 L round-bottomed Schlenk flask, equipped with an egg-shaped, PTFE-coated magnetic stir bar (3 cm), is charged with 1-(Pyrrolidin-1-yl)undec-10-en-1-one (1) (18.5 g, 78.0 mmol, 1.00 equiv) and TEMPO (26.8 g, 172 mmol, 2.20 equiv) (Figure 3A) (Note 18). The flask, which is connected to a vacuum-nitrogen manifold (Schlenk line) using rubber tubing, is sealed with a rubber septum. The flask is subsequently evacuated and refilled with nitrogen three times, after which anhydrous dichloromethane (Note 4) is added via cannula (0.8 ⌀ mm) (Figure 3B), followed by 2-fluoropyridine (Note 19) (7.60 g, 6.70 mL, 78.0 mmol, 1.00 equiv) in one portion via syringe (10 mL syringe with a 0.8 ⌀ mm needle). The flask is then cooled in a water-ice bath, while being kept under positive pressure of nitrogen (connected to the Schlenk line). Trifluoromethanesulfonic anhydride (14.4 mL, 86.0 mmol, 1.10 equiv) (Notes 6, 20 and 21) is added dropwise via syringe (20 mL syringe with a 0.8 ⌀ mm needle) over the course of 10 min while stirring (500 rpm) (Figure 3C), after which the mixture is allowed to warm to room temperature (23 °C) and is stirred at this temperature for 14 h (Note 22). After this time, water (500 mL) is added in one portion and stirring (1000 rpm) is continued for an additional 15 min (Figure 3D).

Figure 3. Reaction setup: A) after TEMPO addition; B) During CH₂Cl₂ addition; C) After trifluoromethanesulfonic anhydride addition; D) After water addition (photos provided by submitters)

Diethyl ether (300 mL) is added, the phases are separated, and the organic phase is sequentially washed with saturated aqueous NaHCO₃ (250 mL) and brine (100 mL). The washed solution is dried over anhydrous MgSO₄ (5 g) and filtered via gravitational filtration using a glass funnel equipped with filter paper. The filtrate is concentrated by rotary evaporation (450 mmHg at 40 °C, followed by 8 mmHg mbar at 40 °C), affording a thick orange oil. The oil mixed with heptane (5 mL) is loaded onto a silica gel column (approximately 500 ± 20 g, column dimensions: 8.5 x 25 cm, equilibrated with heptane) and ca. 100 mL fractions are collected (Figure 4A). The column is first eluted with pure heptane (1 L), which is discarded, followed by an eluent of 10% EtOAc in heptane (4 L) and then 20% EtOAc in heptane for the remainder of the separation (6 L). Fractions 22-95 (Figure 4B) are combined (Note 23), and the solvent is removed by rotary evaporation (120 mmHg at 40 °C and followed by 0.8 mmHg at 40 °C) and by high vacuum (ca. 0.05 mmHg) at room temperature (23 °C) for 6 h to obtain the product 2 as an orange oil (25.1 g, 82%) (Figure 4C) (Notes 17, 24 and 25).

Figure 4. A) Chromatography setup; B) TLC analysis of collected fractions; C) Product in a 100 mL flask (photos provided by submitters)

C. 1-(Pyrrolidin-1-yl)undec-10-ene-1,2-dione (3). A 250 mL, round-bottomed flask that is open to air is equipped with an egg-shaped, PTFE-coated magnetic stir bar (3 cm). the flask is charged with 1-(pyrrolidin-1-yl)-2-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)undec-10-en-1-one 2 (9.80 g, 25.0 mmol, 1.00 equiv), dichloromethane (50 mL) and deionized water (50 mL). The resulting mixture is stirred (800 rpm) and magnesium monoperoxyphthalate hexahydrate (Note 26) (30.9 g, 80% purity, 50.0 mmol, 2.00 equiv) is added in 10 portions over the course of 5 min. The resulting suspension is stirred under air at room temperature (23 °C) for 3 h (Note 27). The reaction mixture is diluted with EtOAc (250 mL) and a saturated aqueous solution of Na₂SO₃(150 mL) (Note 28) is added while stirring is continued for 10 min. The phases are then separated, and the organic phase is sequentially washed with saturated aqueous Na₂CO₃ (2 x 150 mL) (Note 29), 1 M HCl (2 x 150 mL) and brine (100 mL). The washed solution is dried over anhydrous MgSO₄ (5 g) and filtered via gravitational filtration using a glass funnel equipped with filter paper (Note 12). The filtrate is concentrated by rotary evaporation (450 mmHg at 40 °C, followed by 120 mmHg at 40 °C), affording a thick orange oil. The oil is mixed with heptane (5 mL) and then loaded onto a silica gel column (approximately 200 ± 10 g, column dimensions: 6 x 18 cm, equilibrated with heptane) (Figure 5B). The column is then eluted with heptane (500 mL) and a mixture of 10% EtOAc in heptane (500 mL), with all the eluent being discarded. At this point 80 mL fractions are collected as the column is eluted with a mixture of 10% EtOAc in heptane (800 mL), followed by a mixture of 20% EtOAc in heptane (2 L) for the remainder of the separation. Fractions 22-38 (confirmed by TLC, 20% EtOAc in heptane, silica on aluminum, R_f = 0.63, KMnO₄ stain) (Figure 5C) are collected and the solvent is removed by rotary evaporation (120 mmHg at 40°C, followed by 0.8 mmHg at 40 °C). The residue is exposed to high vacuum (ca. 0.05 mmHg) at room temperature (23 °C) for 6 h to obtain product 3 as a slightly yellow oil (3.62 g, 58%) (Figure 5D) (Notes 17 and 30).

Figure 5. A) Reaction setup after Na₂SO₃ addition; B) Chromatography setup; C) TLC analysis of collected fractions; D) Product in a 16 mL vial (photos provided by submitters)

D. 2-Hydroxy-1-(pyrrolidin-1-yl)undec-10-en-1-one (4). A 250 mL, round-bottomed flask that is open to air is equipped with an egg-shaped, PTFE-coated magnetic stir bar (3 cm) and charged with 1-(pyrrolidin-1-yl)-2-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)undec-10-en-1-one 2 (9.80 g, 25.0 mmol, 1.00 equiv) (Figure 6A), water (50 mL) and acetic acid (50 mL) (Note 31) (Figure 6B). The resulting mixture is stirred (600 rpm) open to air, and zinc dust (16.3 g, 250 mmol, 10.0 equiv) (Note 32) is added in 8 portions over the course of 5 min. The flask is loosely fitted with a PE stopper (Note 33) and stirred at 50 °C for 2 h under air (Figure 6C).

Figure 6. Reaction setup: A) After substrate addition; B) After acetic acid addition; C) After zinc addition (photos provided by submitters)

After cooling to room temperature (23 °C), excess zinc dust is filtered off via gravitational filtration, into a 500 mL round-bottomed flask, using a glass funnel equipped with filter paper (Note 12) (Figure 7A) and the reaction flask is rinsed with aqueous acetic acid (1:1 v/v, 2 x 10 mL). Then, the volume of the filtrate is reduced by approximately two thirds by rotary evaporation (55 mmHg at 50 °C) (Figure 7B). Dichloromethane (150 mL) is added, and the mixture is carefully neutralized by addition of saturated NaHCO₃ (ca. 70 mL) until pH 4 is reached (Note 34). The phases are separated through use of a separatory funnel, and a half-saturated sodium potassium tartrate solution (200 mL) (Note 35) is added to the organic layer (in a 500 mL round-bottomed flask). The biphasic mixture is stirred for 3 h at room temperature, during which time a precipitate forms. The phases are separated using a separatory funnel (whereby the precipitate is collected together with the dichloromethane phase), and the aqueous phase is extracted with dichloromethane (3 x 100 mL) (Figure 7C) (Notes 17 and 36).

Figure 7. A) Filtration of excess zinc; B) After partial evaporation; C) After treatment with tartrate solution (photos provided by submitters)

The combined organic solutions (still containing the precipitate) are dried over anhydrous MgSO₄ (5 g) and the solids are filtered off via gravitational filtration using a glass funnel equipped with filter paper (Note 12). The filtrate is concentrated by rotary evaporation (450 mmHg at 40 °C and followed by 0.8 mmHg at 40 °C, followed by high vacuum (ca. 0.05 mmHg) at room temperature (23 °C) for 14 h), to afford product 4 as an-off white solid (5.46 g, 86%) (Figure 8) that requires no further purification (Note 37).

Figure 8. Product 4 (photo provided by submitters)

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/prudent-practices-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 10-undecenoyl chloride, pyrrolidine, trimethylamine, 2-fluoropyridine, trifluoromethanesulfonic anhydride, 2,2,6,6-tetramethylpiperidine 1-oxyl, magnesium monoperoxyphthalate hexahydrate, zinc, acetic acid dichloromethane, diethyl ether, sodium bicarbonate, sodium carbonate, hydrochloric acid, sodium potassium tartrate, heptane, ethyl acetate and silica gel.

2. Pyrrolidine was purchased from Merck (purity >99.0) and used as received.

3. Triethylamine was purchased from Fischer Chemicals, AG (purity >99.0) and used as received.

4. Dichloromethane (>99.9%) was purchased from Honeywell (dried by mBraun SPS) and stored under argon.

5. 10-Undecenoyl chloride was purchased from TCI (purity >98.0) and used as received.

6. Excess reagent remaining in the needle was quenched with water.

7. Diethyl ether was purchased from Honeywell (ACS reagent, purity >99.8) and used as received.

8. Aqueous HCl (32%) was purchased from VWR and diluted to 1M.

9. Saturated aqueous NaHCO₃ was purchased from Honeywell (purity >99.7) and used as received.

10. Brine was purchased from Honeywell (purity >99.5) and used as received.

11. Anhydrous MgSO₄was purchased from Merck (purity >98.0) and used as received.

12. Filter paper (MN 615 ¼, >4 µm) was purchased from Macherey-Nagel.

13. Heptane was purchased from Honeywell (purity >99.7) and used as received.

14. Silica gel was purchased from Merck (0.063-0.200 mm).

15. Ethyl acetate was purchased from Honeywell (purity >99.7) and used as received.

16. Characterization data for 1: ¹H NMR pdf (400 MHz, CDCl₃) δ: 5.80 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.00 - 4.85 (m, 2H), 3.41 (dt, J = 20.4, 6.70 Hz, 4H), 2.28 - 2.20 (m, 2H), 2.03 (dd, J = 14.3, 6.9 Hz, 2H), 1.96 - 1.88 (m, 2H), 1.86 - 1.78 (m, 2H), 1.70 - 1.58 (m, 2H), 1.40 - 1.21 (m, 10H). ¹³C NMR pdf (101 MHz, CDCl₃) d: 171.9, 139.3, 114.2, 46.7, 45.6, 34.9, 33.9, 29.6, 29.6, 29.5, 29.2, 29.0, 26.2, 25.0, 24.5. IR (neat) ν_max: 2973, 2925, 2870, 1650, 1439, 1132, 991, 909, 712 cm^-1. HRMS (ESI⁺, m/z): [M+H]⁺ calculated for [C₁₅H₂₈NO]⁺: 238.2165, found: 238.2168. TLC R_f = 0.25 (50% EtOAc in heptane, silica on aluminum, (Note 17) KMnO₄ stain). Purity was assessed at >99% by quantitative ¹H NMR pdf spectroscopy using ethylene carbonate (>99%) as an internal standard.

17. TLC analysis is performed on TLC plates purchased from Merck (TLC Silica gel 60 F₂₅₄).

18. TEMPO was purchased from Fluorochem (purity 99%) and used as received.

19. 2-Fluoropyridine was purchased from Fluorochem (purity 98%) and used as received.

20. Trifluoromethanesulfonic anhydride was purchased from Fluorochem (purity 99%) and used as received.

21. Trifluoromethanesulfonic anhydride hydrolyses under air but can be reformed and purified according to a procedure reported by Stang and Dueber in Org. Synth. 1974, 54, 79.

22. Maximum conversion was confirmed via ¹H NMR analysis of the crude reaction mixture.

23. The product elution can be monitored by TLC (50% EtOAc in heptane, R_f = 0.70, silica on aluminum, KMnO₄ stain). The product is closely followed by an unidentified by-product. The TLC analysis should be conducted and evaluated carefully, so as to not collect the by-product in the pooled fractions.

24. Slight changes in color might be observed between different runs through small amounts of an unidentified impurity.

25. Characterization data for 2: ¹H NMR pdf (400 MHz, CDCl₃) δ: 5.81 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 4.96 (ddd, J = 13.6, 10.2, 1.4 Hz, 2H), 4.40 (dd, J = 10.2, 4.7 Hz, 1H), 3.94 (dt, J = 10.2, 6.6 Hz, 1H), 3.59 - 3.36 (m, 3H), 2.03 (dd, J = 14.4, 7.0 Hz, 2H), 1.98 - 1.90 (m, 2H), 1.90 - 1.73 (m, 4H), 1.46 - 0.97 (m, 28H). ¹³C NMR pdf (101 MHz, CDCl₃) δ: 171.3, 138.9, 113.8, 83.3, 60.2, 58.9, 46.5, 45.4, 40.3, 40.0, 33.4, 33.1, 32.4, 31.3, 29.4, 29.0, 28.7, 28.5, 25.8, 24.8, 23.8, 20.0, 19.7, 16.8.IR (neat) ν_max: 2973, 2925, 2870, 2853, 1650, 1439, 1375, 1339, 1132, 991, 909, 711 cm^-1. HRMS (ESI⁺, m/z): [M+H]⁺ calculated for [C₂₄H₄₅N₂O₂]⁺: 393.3476, found: 393.3479. R_f = 0.70 (50% EtOAc in heptane, silica on aluminum, (Note 17) KMnO₄ stain). Purity was assessed at >99% by quantitative ¹H NMR pdf using ethylene carbonate (>99%) as an internal standard. TLC

26. Magnesium monoperoxyphthalate hexahydrate is purchased from Fluorochem (purity 80%) and used as received.

27. Full conversion is reached after 3 h. TLC analysis was not used for analysis since the starting material and the product possess similar R_f values.

28. Sodium sulfite was purchased from Merck (>98%) and used to prepare the saturated solution.

29. Sodium carbonate was purchased from Merck (>99.5%) and used to prepare the saturated solution.

30. Characterization data for 3: ¹H NMR pdf (400 MHz, CDCl₃) δ: 5.78 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.02 - 4.86 (m, 2H), 3.58 (t, J = 7.4, Hz, 2H), 3.50 (t, J = 6.9 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.02 (dd, J = 14.4, 6.9 Hz, 2H), 1.96 - 1.90 (m, 2H), 1.90 - 1.83 (m, 2H), 1.62 - 1.55 (m, 2H), 1.40 - 1.25 (m, 8H). ¹³C NMR pdf (101 MHz, CDCl₃) δ: 201.2, 163.3, 139.2, 114.3, 47.4, 46.4, 39.4, 33.9, 29.3, 29.2, 29.0, 28.9, 26.5, 23.7, 23.1. IR (neat) ν_max: 3074, 2974, 2926, 2854, 1713, 1635, 1440, 1339, 1225, 995, 909 cm^-1. HRMS (ESI⁺, m/z): [M+H]⁺ calculated for [C₁₅H₂₆NO₂Na]⁺: 252.1958, found: 252.1957. TLC R_f = 0.63 (50% EtOAc in heptane, silica on aluminum, (Note 17) KMnO₄ stain). Purity was assessed at >99% by quantitative ¹H NMR pdf spectroscopy using ethylene carbonate (>99%) as an internal standard.

31. Acetic acid (glacial, 100%) was purchased from Merck and used as received.

32. Zinc dust was purchased from Merck (dust < 10 µm, purity >98%) and used as received.

33. Slow evolution of hydrogen gas can be observed.

34. Higher pH can lead to lower yields.

35. Sodium potassium tartrate was purchased from Merck (99%) and used as received to prepare the solution.

36. It can take several minutes until the two phases have separated in the separatory funnel.

37. Characterization data for 4: ¹H NMR pdf (400 MHz, CDCl₃) δ: 5.77 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.02 - 4.82 (m, 2H), 4.14 (dd, J = 7.5, 2.8 Hz, 1H), 3.62 - 3.49 (m, 1H), 3.50 - 3.38 (m, 2H), 3.32 (dt, J = 10.2, 6.8 Hz, 1H), 2.05 - 1.78 (m, 6H), 1.67 - 1.16 (m, 13H). ¹³C NMR pdf (101 MHz, CDCl₃) δ: 173.1, 139.2, 114.2, 69.4, 46.3, 46.0, 34.5, 33.8, 29.4 (2C), 29.1, 29.0, 26.1, 25.1, 23.9. IR (neat) ν_max: 3441, 2919, 2850, 1625, 1453, 1385, 1197, 1078, 992, 923, 732, 463 cm^-1. HRMS (ESI⁺, m/z): [M+H]⁺ calculated for [C₁₅H₂₈NO₂]⁺: 254.2115, found: 254.2115. TLC R_f = 0.23 (50% EtOAc in heptane, silica on aluminum, (Note 17) KMnO₄ stain). Purity was assessed at >99% by quantitative ¹H NMR pdf using ethylene carbonate (>99%) as an internal standard.

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

Selective oxidation reactions are valuable transformations in organic synthesis.² Particularly, the α-keto amide functionality has observed a spike in popularity in the synthetic chemistry community in recent years.³ Additionally, the α-hydroxy carbonyl moiety represents a useful template for further synthetic development.⁴Direct oxidation methodologies to access α-keto amides are scarce and limited to specific substrates,⁵ whereas α-hydroxy carbonyl derivatives are generally obtained from the parent compounds utilizing enol/enolate chemistry.^4b,6 This effectively limits the availability of amides as substrates for such transformations, due to their limited susceptibility to enolization.

Amide activation using triflic anhydride is a distinctive synthetic approach employed by multiple research groups in order to transform amides via chemoselective cycloaddition or nucleophilic addition processes.⁷ Furthermore, formation of an electrophilic enolonium species under certain conditions can trigger Umpolung reactivity at the α-position of amides activated under this paradigm.⁸ We have previously developed a chemoselective oxidation of amides to α-keto amides and α-hydroxy amides. Specifically, the use of TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl) during triflic anhydride-mediated amide activation provides the corresponding α-(tetramethylpiperidin-1-yl)oxyamides (Scheme 1A).⁹ Reductive cleavage conditions lead to the corresponding α-hydroxy amides, thus positioning the tetramethylpiperidine (TMP) moiety as a "protecting group" for the hydroxy function. Alternatively, oxidative treatment of the oxyaminated amides provides access to α-keto amides (Scheme 1B). This synthetic strategy, based on chemoselective amide activation using triflic anhydride along with the use of an oxidant, represents a useful tool potentially applicable to virtually any type of tertiary amide. The utility of such an approach is showcased by further transformations of the oxyaminated amides into synthetically useful building blocks accessible employing commonly used reagents.

Scheme 1. A) Amide scope in α-OTMP amide oxidation; B) Synthesis of α-hydroxy and α-keto amides from α-OTMP amide

References and Notes

Department of Organic Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria. E-Mail: nuno.maulide@univie.ac.at, Homepage: http://maulide.univie.ac.at. Generous support of this research by the EU (VINCAT CoG 682002 to N.M.), the Austrian Science Fund (P32607), Covestro AG, and the University of Vienna (Uni:docs fellowship to M.L.) is acknowledged. We are grateful to the University of Vienna for its continued and generous support of our research programs.
White, M. C. Adding Aliphatic C-H Bond Oxidations to Synthesis. Science 2012, 335, 807−809.
(a) De Risi, C.; Pollini, G. P.; Zanirato, V. Recent Developments in General Methodologies for the Synthesis of α-Ketoamides. Chem. Rev. 2016, 116, 3241−3305; (b) Kumar, D.; Vemula, S. R.; Cook, G. R. Recent Advances in the Catalytic Synthesis of α-Ketoamides. ACS Catal. 2016, 6, 4920−4945; (c) Zhang, C.; Jiao, N. Dioxygen Activation under Ambient Conditions: Cu-Catalyzed Oxidative Amidation−Diketonization of Terminal Alkynes Leading to α-Ketoamides. J. Am. Chem. Soc. 2010, 132, 28−29; (d) Du, F.-T.; Ji, J.-X. Copper-catalyzed direct oxidative synthesis of α-ketoamides from aryl methyl ketones, amines, and molecular oxygen. Chem. Sci. 2012, 3, 460−465; (e) Deshidi, R.; Kumar, M.; Devari, S.; Shah, B. A. A general metal free approach to α-ketoamides via oxidative amidation-diketonization of terminal alkynes. Chem. Commun. 2014, 50, 9533−9535; (f) Liu, L.; Du, L.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. Metal-Free Tandem Oxidative Aryl Migration and C-C Bond Cleavage: Synthesis of α-Ketoamides and Esters from Acrylic Derivatives. Org. Lett. 2014, 16, 5772−5775; (g) Li, W.; Duan, Z.; Zhang, X.; Zhang, H.; Wang, M.; Jiang, R.; Zeng, H.; Liu, C.; Lei, A. From Anilines to Isatins: Oxidative Palladium-Catalyzed Double Carbonylation of C-H Bonds. Angew. Chem. Int. Ed. 2015, 54, 1893−1896; (h) Wang, Z.; Liu, C.; Huang, Y.; Hu, Y.; Zhang, B. Covalent triazine framework-supported palladium as a ligand-free catalyst for the selective double carbonylation of aryl iodides under ambient pressure of CO. Chem. Commun. 2016, 52, 2960−2963; (i) Nagaki, A.; Takahashi, Y.; Yoshida, J. Generation and Reaction of Carbamoyl Anions in Flow: Applications in the Three-Component Synthesis of Functionalized α-Ketoamides. Angew. Chem. Int. Ed. 2016, 55, 5327−5331; (j) Ma, F.; Liu, H.; Chen, J. Convenient method for the preparation of secondary α-ketoamides via aminocarbonylation of acid chlorides with carbamoylsilane. Tetrahedron Lett. 2016, 57, 5246−5250; (k) Kou, K. G.M.; Le, D. N.; Dong, V. M. Rh(I)-Catalyzed Intermolecular Hydroacylation: Enantioselective Cross-Coupling of Aldehydes and Ketoamides. J. Am. Chem. Soc. 2014, 136, 9471−9476; (l) Goudedranche, S.; Pierrot, D.; Constantieux, T.; Bonne, D.; Rodriguez, J. A temporary-bridge strategy for enantioselective organocatalyzed synthesis of aza-seven-membered rings. Chem. Commun. 2014, 50, 15605−15608; (m) Echave, H.; López, R.; Palomo, C. Bifunctional Brønsted Base Catalyzes Direct Asymmetric Aldol Reaction of α-Keto Amides. Angew. Chem. Int. Ed. 2016, 55, 3364−3368; (n) Xu, X.-M.; Zhao, L.; Zhu, J.; Wang, M.-X. atalytic Asymmetric Tandem Reaction of Tertiary Enamides: Expeditious Synthesis of Pyrrolo[2,1-a]isoquinoline Alkaloid Derivatives. Angew. Chem. Int. Ed. 2016, 55, 3799−3803; (o) Chen, Q.; Tang, Y.; Huang, T.; Liu, X.; Lin, L.; Feng, X. Copper/Guanidine-Catalyzed Asymmetric Alkynylation of Isatins. Angew. Chem. Int. Ed. 2016, 55, 5286−5289; (p) Du, Y.; Yu, A.; Jia, J.; Zhang, Y.; Meng, X. Direct N-H/α,α,β,β-C(sp3)-H functionalization of piperidine via an azomethine ylide route: synthesis of spirooxindoles bearing 3-substituted oxindoles. Chem. Commun. 2017, 53, 1684−1687.
(a) Palomo, C.; Oiarbide, M.; García, J. M. α-Hydroxy ketones as useful templates in asymmetric reactions. Chem. Soc. Rev. 2012, 41, 4150−4164; (b) Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek, E. Org. React. 2003, 62.
(a) Song, B.; Wang, S.; Sun, C.; Deng, H.; Xu, B. Cesium carbonate promoted aerobic oxidation of arylacetamides: an efficient access to N-substituted α-keto amides. Tetrahedron Lett. 2007, 48, 8982−8986; (b) Shao, J.; Huang, X.; Wang, S.; Liu, B.; Xu, B. A straightforward synthesis of N-monosubstituted α-keto amides via aerobic benzylic oxidation of amides. Tetrahedron 2012, 68, 573−579.
(a) Smith, A. M. R.; Hii, K. K. Transition Metal Catalyzed Enantioselective α-Heterofunctionalization of Carbonyl Compounds. Chem. Rev. 2011, 111, 1637−1656; (b) Vilaivan, T.; Bhanthumnavin, W. Organocatalyzed Asymmetric α-Oxidation, α-Aminoxylation and α-Amination of Carbonyl Compounds. Molecules 2010, 15, 917−958.
(a) Movassaghi, M.; Hill, M. D. Synthesis of Substituted Pyridine Derivatives via the Ruthenium-Catalyzed Cycloisomerization of 3-Azadienynes. J. Am. Chem. Soc. 2006, 128, 4592−4593; (b) Movassaghi, M.; Hill, M. D.; Ahmad, O. K. Direct Synthesis of Pyridine Derivatives. J. Am. Chem. Soc. 2007, 129, 10096−10097; (c) Medley, J. W.; Movassaghi, M. Direct Dehydrative N-Pyridinylation of Amides. J. Org. Chem. 2009, 74, 1341−1344; (d) Mewald, M.; Medley, J. W.; Movassaghi, M. Concise and Enantioselective Total Synthesis of (−)-Mehranine, (−)-Methylenebismehranine, and Related Aspidosperma Alkaloids. Angew. Chem. Int. Ed. 2014, 53, 11634−11639; (e) White, K. L.; Mewald, M.; Movassaghi, M. Direct Observation of Intermediates Involved in the Interruption of the Bischler-Napieralski Reaction. J. Org. Chem. 2015, 80, 7403−7411; (f) White, K. L.; Movassaghi, M. Concise Total Syntheses of (+)-Haplocidine and (+)-Haplocine via Late-Stage Oxidation of (+)-Fendleridine Derivatives. J. Am. Chem. Soc. 2016, 138, 11383−11389; (g) Barbe, G.; Charette, A. B. Highly Chemoselective Metal-Free Reduction of Tertiary Amides. J. Am. Chem. Soc. 2008, 130, 18−19; (h) Pelletier, G.; Bechara, W. S.; Charette, A. B. Controlled and Chemoselective Reduction of Secondary Amides. J. Am. Chem. Soc. 2010, 132, 12817−12819; (i) Bechara, W. S.; Pelletier, G.; Charette, A. B. hemoselective synthesis of ketones and ketimines by addition of organometallic reagents to secondary amides. Nat. Chem. 2012, 4, 228−234; (j) Xiao, K.-J.; Wang, A.-E.; Huang, P.-Q. Direct Transformation of Secondary Amides into Secondary Amines: Triflic Anhydride Activated Reductive Alkylation. Angew. Chem. Int. Ed. 2012, 51, 8314−8317; (k) Peng, B.; Geerdink, D.; Maulide, N. Electrophilic Rearrangements of Chiral Amides: A Traceless Asymmetric α-Allylation. J. Am. Chem. Soc. 2013, 135, 14968−14971; (l) Huang, P.-Q.; Huang, Y.-H.; Xiao, K.-J.; Wang, Y.; Xia, Y.-E. A General Method for the One-Pot Reductive Functionalization of Secondary Amides. J. Org. Chem. 2015, 80, 2861−2868; (m) Lumbroso, A.; Behra, J.; Kolleth, A.; Dakas, P.-Y.; Karadeniz, U.; Catak, S.; Sulzer-Mossé, S.; De Mesmaeker, A. Access to functionalized 3-amino-benzothiophenes using keteniminium intermediates. Tetrahedron Lett. 2015, 56, 6541−6545; (n) Kolleth, A.; Lumbroso, A.; Tanriver, G.; Catak, S.; Sulzer-Mossé, S.; De Mesmaeker, A. Synthesis of amino-cyclobutanes via [2 + 2] cycloadditions involving keteniminium intermediates. Tetrahedron Lett. 2016, 57, 2697−2702; (o) Huang, P.-Q.; Huang, Y.-H.; Xiao, K.-J. Metal-Free Intermolecular Coupling of Arenes with Secondary Amides: Chemoselective Synthesis of Aromatic Ketimines and Ketones, and N-Deacylation of Secondary Amides. J. Org. Chem. 2016, 81, 9020−9027; (p) Kaiser, D.; Maulide, N. J. Org. Chem. 2016, 81, 4421−4428; (q) Tona, V.; de la Torre, A.; Padmanaban, M.; Ruider, S.; González, L.; Maulide, N. Chemo- and Stereoselective Transition-Metal-Free Amination of Amides with Azides. J. Am. Chem. Soc. 2016, 138, 8348−8351; (r) Kaiser, D.; Bauer, A.; Lemmerer, M.; Maulide, N. Amide activation: an emerging tool for chemoselective synthesis. Chem. Soc. Rev. 2018, 47, 7899-7925.
(a) Patil, D. V.; Kim, S. W.; Nguyen, Q. H.; Kim, H.; Wang, S.; Hoang, T.; Shin, S. Brønsted Acid Catalyzed Oxygenative Bimolecular Friedel-Crafts-type Coupling of Ynamides. Angew. Chem. Int. Ed. 2017, 56, 3670−3674; (b) Kaiser, D.; de la Torre, A.; Shaaban, S.; Maulide, N. Metal-Free Formal Oxidative C-C Coupling by In Situ Generation of an Enolonium Species. Angew. Chem. Int. Ed. 2017, 56, 5921−5925; (c) Chen, X.; Ruider, S. A.; Hartmann, R. W.; González, L.; Maulide, N. Metal-Free meta-Selective Alkyne Oxyarylation with Pyridine N-Oxides: Rapid Assembly of Metyrapone Analogues. Angew. Chem. Int. Ed. 2016, 55, 15424−15428; (d) Gonçalves, C. R.; Lemmerer, M.; Teskey, C. J.; Adler, P.; Kaiser, D.; Maryasin, B.; González, L.; Maulide, N. Unified Approach to the Chemoselective α-Functionalization of Amides with Heteroatom Nucleophiles. J. Am. Chem. Soc. 2019, 141, 18437-18443.
de la Torre, A.; Kaiser, D.; Maulide, N. Flexible and Chemoselective Oxidation of Amides to α-Keto Amides and α-Hydroxy Amides. J. Am. Chem. Soc. 2017, 139, 6578−6581.

Appendix
Chemical Abstracts Nomenclature (Registry Number)

10-Undecenoyl chloride; (38460-95-6)

Pyrrolidine; (123-75-1)

Triethylamine; (121-44-8)

2-Fluoropyridine; (372-48-5)

Trifluoromethanesulfonic anhydride; (358-23-6)

2,2,6,6-Tetramethylpiperidine 1-oxyl; (2564-83-2)

Magnesium monoperoxyphthalate hexahydrate; (84665-66-7)

Zinc; (7440-66-6)

	Miran Lemmerer studied chemistry at the University of Vienna. During his studies he performed an Erasmus exchange semester in Lund, Sweden where he focused his studies on organic- and biological chemistry. Under the supervision of Prof. Maulide, he completed his Masters thesis in 2018, developing a protocol for α-amination of amides via Umpolung. Currently, he is pursuing his Ph.D. degree in the group of Prof. Maulide, investigating novel methods based on the electrophilic activation of amides.
	Ján Matyašovský was born in Partizanske, Slovakia. He received his Engineering Degree at the Slovak Technical University in Bratislava, specializing in organic chemistry. In 2020, he obtained his Ph.D. degree at the Charles University in Prague for his work on synthesis of modified nucleic acids at the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences under supervision of Prof. Michal Hocek. He currently occupies a post-doctoral position in the research group of Professor Nuno Maulide at the University of Vienna. His current research interests focus on the development of new methodologies for organic synthesis.
	Roberto Tinelli received his MSc from the University of Pavia in 2020, where, under the supervision of Prof. Ravelli, he worked on the development of new substrates for the Paternò-Büchi reaction. He is currently pursuing his Ph.D. studies at the University of Vienna under the supervision of Prof. Maulide. His current research focuses on the chemistry of thioalkynes and related high-energy intermediates.
	After obtaining his Ph.D. at the Université catholique de Louvain under the supervision of Prof. István E. Markó in 2007 Nuno Maulide pursued a postdoctoral position in the group of Prof. Barry M. Trost at Stanford University. In 2009, he started his independent career at the Max-Planck Institut für Kohlenforschung and only 4 years later, in 2013 he became a Full Professor at the University of Vienna. His research interests are broadly spread in the field of organic chemistry and include the development of new reaction methods, the total synthesis of natural compounds and medicinal chemistry driven investigations. He is a member of the Board of Editors for Organic Syntheses (2018) as well as an Associate Editor of Organic Letters (2018) and JACS AU (2020). Beyond his scientific endeavors, for which he received 3 ERC grants and multiple awards like the Tetrahedron Young Investigator Award (2020), he is also heavily involved in knowledge transfer to the public. For his great conveyance of Science, also coupled with his other passion, the piano, he was appointed Scientist of the Year in Austria (2018).
	Colin Knus was born in Switzerland and joined the Nevado group in 2022 as a Lab Technician. He is currently a second-year student of his Apprenticeship course. He enjoys chemistry, travelling around on his motorbike and snowboarding.
	Dr. Jaime Martín was born In León, Spain. In 2020, he obtained his Ph.D. in Inorganic Chemistry at the University of Zaragoza. Thereafter, he joined the group of Prof. Cristina Nevado at the University of Zurich as a Postdoctoral Associate. His main research interest is focused on the study of new gold(III) complexes, their reactivity and their application in catalysis.
	Jorge A. González was born in Xalapa, Mexico. He completed his Undergraduate Degree in Chemistry at the National and Autonomous University of Mexico in 2011. He obtained his Ph.D. at the University of Edinburgh in 2016. He is currently a postdoctoral associate research associate in the group of Prof. Cristina Nevado.

Notes

References/EndNotes

Article Compounds

Authors