Aza-Rubottom Oxidation: Synthetic Access to Primary α-Aminoketones

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Aza-Rubottom Oxidation: Synthetic Access to Primary #-Aminoketones Zhe Zhou, Qing-Qing Cheng, and László Kürti J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Jan 2019 Downloaded from http://pubs.acs.org on January 29, 2019

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Journal of the American Chemical Society

Aza-Rubottom Oxidation: Synthetic Access to Primary αAminoketones Zhe Zhou, Qing-Qing Cheng and László Kürti* Department of Chemistry, Rice University
BioScience Research Collaborative
6500 Main Street, Houston, TX 77030 (USA) E-mail: [email protected]

Supporting Information Placeholder ABSTRACT: An aza analogue of the Rubottom oxidation is reported. This facile transformation takes place at ambient temperature and directly converts silyl enol ethers to the corresponding primary α-aminoketones. The use of hexafluoro isopropanol (HFIP) as the solvent is essential for the success of this reaction. Overall this process is well-suited for the aza-functionalization and derivatization of complex organic molecules.

O-phosphinylhydroxylamine) are usually very volatile and their use is limited due to safety concerns (i.e., toxicity). One unique approach developed by the Wirth group uses a hypervalent iodine reagent to facilitate an intramolecular umpolung reaction to access α-aminoketones, although the amino group must be fully substituted.7 Other noteworthy approaches to access secondary and tertiary α-amino carbonyl compounds include several types of copper-catalyzed coupling reactions.8 A. Typical Two-Step Approaches to Primary α-Amino Ketones O

The alpha-aminoketone moiety is commonly found in biological molecules, natural products and active pharmaceutical ingredients. Despite their apparent importance, synthetic 1 access to these compounds is not always straightforward. This is especially evident when the desired amino ketones have a primary amino group attached to a fully substituted α-carbon atom. The most common strategy for synthesizing these compounds involves a two-step approach, in which either an azido,2 a nitro,3 or a hydroxylamino group4 is first installed at the α-position. A subsequent hydrogenation, usually catalyzed by a transition metal such as Pd, Pt or Raney Ni, is then carried out to obtain the corresponding primary α-aminoketone (Figure 1, A). Aside from the added steps, this approach also has limitations such as the lack of chemoselectivity during the reduction and the potential instability of the azido- or nitro- intermediates. Significant efforts have been devoted into making αhydrazinyl compounds from ketones and azodicarbonyl compounds such as DEAD under basic or organocatalytic conditions (Figure 1, B).5 Although this type of αhydrazination reaction is generally high-yielding and can be rendered enantioselective, it is far from trivial to cleave the N-N bond and reveal the desired primary amino ketones. An ideal reaction should be able to directly install the primary amino group without the need to perform an additional reduction or N-deprotection. A few such examples have been 6 reported in the literature. The common strategy is to trap the enolates generated from the corresponding ketones with an electrophilic nitrogen source. However, good yields can only be obtained with ketones that can form stable enolates, such as malonates, phenyl acetates and phenylacetonitriles. Moreover, the required aminating reagents (i.e. chloramine,

R3 N3

H2/Pd/BaSO4

R3 NO2 R2

Zn/HOAc

R1 R2 O

O

R3 H R2

R1

R1

O R2

O R1 R2

R1

R3 NH2

Raney Ni

R3 NOH Cbz

B. Asymmetric Synthesis of Primary α-Amino Ketones O R1 R

R3 H 2

Boc

N N

Boc O R1

Chiral Catalyst

R3 * NBoc 2 R NHBoc

TFA DCM

H2, Raney Ni MeOH, sonication

O R1

R3 * NH 2 R2

C. The Rubottom Oxidation and the Proposed “Aza-Rubottom Oxidation” R3 R O Si R R1 R

R2

R3 R O Si R R R1

R2

DMDO or mCPBA

Aminating Reagent

O R O Si R R1 R

HN R O Si R R1 R

O

R3 R2

R1

R2

R1

R2

R3 OH

Rubottom Oxidation

O

R3

R2

R3 NH2

Aza-Rubottom Oxidation

Figure 1. Existing methods for the synthesis of α-aminoketones and the proposed “aza-Rubottom oxidation” Contrary to the generally difficult α-amination reactions, the α-hydroxylation of ketones is a well-established transformation that today is considered to be trivial. Two general approaches are available, namely the trapping of an in-situ 9 generated enolate with Davis oxaziridine and the Rubottom oxidation in which silyl enol ethers are oxidized with either peroxyacids, peroxides or dioxiranes.10 These two approaches have wide applicability, and both have been successfully used numerous times, even in the synthesis of extremely complex natural products.11

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While limited attempts have been made to mimic the first approach (i.e. the aforementioned trapping of enolates with chloramine or O-phosphinylhydroxylamine), to the best of our knowledge, no systematic studies have been dedicated to developing an amino analogue of the Rubottom oxidation (AKA “Aza-Rubottom oxidation”). Herein, we report our findings in the development of such a transformation. The Rubottom oxidation of silyl enol ethers goes through an epoxide intermediate.10b Presumably, an aza-Rubottom oxidation will go through the corresponding (NH)-aziridine intermediate (Figure 1, C). 12,13 While catalyst-free epoxidation of olefins can be easily achieved with either peracids or dioxiranes, the prevailing wisdom is that NH-aziridination of olefins requires the presence of a transition metal (TM) catalyst.14 Table 1. Optimization of Reaction Conditions. Me

TBSO Ph

Me

O

O

aminating reagent (XONH2) catalyst/additive

NH2

Ph

solvent, rt, 16 h

Et2O

Me Me

1

HCl

NH2

Ph

HCl

Me Me

1a

1b

Aminating Reagent (XONH2) O2N H2 N O O S OH O NO2 H2N O 2 (HOSA) 3 (DPH)

O R

O

NH2 TfOH

4 R = C6H5 5 R = p-NO2C6H4

O NH

6

Entry[a]

XONH2

Catalyst

Additive

1

2 (1.2 equiv)

Rh2(esp)2

pyridine (1.2 equiv)

HFIP

66%

2

2 (2 equiv)

none

pyridine (4 equiv)

HFIP

0b

3

2 (2 equiv)

none

K3PO4 (2 equiv)

HFIP

Traceb

4

2 (1.5 equiv)

none

Cs2CO3 (3 equiv)

HFIP

41%

5

2 (1.5 equiv)

none

Cs2CO3 (3 equiv)

TFE

Trace

6

2 (1.5 equiv)

none

Cs2CO3 (3 equiv)

MeCN

0

7

2 (1.5 equiv)

none

Cs2CO3 (3 equiv)

DCM

0

8

3 (1.5 equiv)

none

none

HFIP

47%

9

3 (1.2 equiv)

none

iPr2NEt (1.5 equiv)

HFIP

85%

10

2 (1.2 equiv)

none

iPr2NEt (1.5 equiv)

HFIP

Trace

11

4 (1.5 equiv)

none

iPr2NEt (3 equiv)

HFIP

17%

12

5 (1.5 equiv)

none

iPr2NEt (3 equiv)

HFIP

10%

13

6 (1.2 equiv)

none

iPr2NEt (1.5 equiv)

HFIP

0

14

3 (1.2 equiv)

none

iPr2NEt (1.5 equiv)

TFE

Trace

15

3 (1.2 equiv)

none

iPr2NEt (1.5 equiv)

MeCN

0

16

3 (1.2 equiv)

none

iPr2NEt (1.5 equiv)

DCM

0

Solvent Yield (%)

[a] Optimization reactions were conducted on a 0.2 mmol scale. Aminating reagent and additives were mixed in 1 mL solvent and stirred at rt for 10 min before the silyl enol ether was added to the mixture. Reactions were stopped after 16 h, and the amine product was converted to its HCl salt after isolation. [b] The silyl ether 1 decomposed to the ketone.

During our ongoing studies of developing enantioselective NH-aziridination reactions, we were surprised to discover that when HFIP is used as the solvent, a noticeable background reaction is present when the olefin substrates are very electron rich. This is especially evident when a tetrasubstituted olefin is used, which can be fully converted to the corresponding NH-aziridine with no transition metal catalyst, albeit at a significantly slower rate. We ruled out the possibility of trace metal contamination in the HFIP by conducting a control experiment using redistilled HFIP, which gave the same result. This background reaction is negligible unless the olefins are very electron-rich (i.e., tetra-alkyl substituted). Realizing that silyl enol ethers are even more electron-rich than fully carbon-substituted olefins, we were curious to see whether they could be aziridinated and in-situ converted to the corresponding α-amino ketones without the use of a transition metal catalyst.15 We started our investigation using silyl enol ether 1 and several aminating reagents (Table 1, 2-6) to determine the optimal reaction conditions (Table 1). Unsurprisingly, the reaction could proceed under virtually the same conditions used in the NH-aziridination reaction14b and give the desired αaminoketone 1a in good yield (Table 1, entry 1). To facilitate the characterization and isolation of the product, we converted the free amine to an HCl salt 1b, which was found to be more stable. The aminating reaction did not proceed when the Rh catalyst was removed (Table 1, entry 2). This is likely due to the desilylation of 1 caused by the acidic reaction mixture of HOSA and HFIP which outcompetes the amination reaction in the absence of a catalyst. Indeed, when a stronger base was used, a decent yield of 1b was obtained (Table 1, entry 4). Next, we examined several different electrophilic aminating reagents. Aminating reagents 2-5 can be considered as the nitrogen analogues of peracids, and we hypothesized that NH-oxaziridine 6, the aza analogue of dioxiranes, may behave like an aminating agent and would transfer the NH unit. The results showed that DPH (3) is the best aminating reagent (Table 1, entry 9), and it gives a better yield than the Rh-catalyzed reaction (Table 1, entry 9 vs 1). Buffering with a base is necessary to minimize desilylation and increase the yield of the desired product (Table 1, entry 9 vs entry 8). NHOxaziridine 6 failed to react (Table 1, entry 13), indicating that the analogy between an NH-oxaziridine and the corresponding dioxirane is merely structural and is not reflected in their reactivity. We also noticed an extreme case of solvent effect in this reaction: HFIP is absolutely essential for the success of this reaction (Table 1, entry 5-7, 14-16), and the mixing of co-solvents is detrimental to the success of this transformation. Next, we explored the scope of the reaction (Scheme 1). Substrates bearing one phenyl group and various alkyl substituents gave good yields under the optimized conditions (Scheme 1, 1b, 7b-9b). It should be noted that an allyl group was unaffected under the reaction conditions (Scheme 1, 7b), demonstrating the reaction’s chemoselectivity, in which a 1 more electron-rich π bond is preferentially oxidized. When R was a substituted phenyl group, we observed a noticeable electronic effect in which electron-rich substrates gave higher yields than electron-poor ones (Scheme 1, 10b vs 12b).

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Journal of the American Chemical Society Heterocycles were tolerated in these reactions and substrates bearing thiophene, imidazole, and benzofuran rings gave satisfactory yields (Scheme 1, 13b-15b). The reaction also worked well when R1, R2 and R3 are all alkyl groups (Scheme 1, 17b and 18b). Finally, an indomethacin-derived substrate 19 was successfully aminated to furnish 19b, demonstrating this transformation’s remarkable functional group tolerance and its potential application in late-stage functionalization of medicinal chemistry intermediates. It should be emphasized that most of these products have been previously unknown.

Scheme 1. Transition Metal-Free Aza-Rubottom Oxidation. R2

TBSO R1

O

DPH (1.2 equiv.) iPr2NEt (1.5 equiv.)

R3

HFIP, rt, 16 h

HCl

NH2

R1

R2

TBSO R1

Catalyst HOSA (1.2 equiv.) Pyridine (2.4 equiv.)

R3

HFIP, rt, 6 h

20-24 1 mmol scale

O

HCl

NH2

R1

Et2O

R2 R3

NH2

HCl

R2 R3

20b-24b

Structures of α-Amino Ketones Compound # [a]: Isolated Yield (%), Catalyst O

R2 R3

O

Structures of α-Amino Ketones Compound # [a]: Isolated Yield (%)

O

O NH2 HCl

CO2Et Me NH2 HCl

1b, 7b-19b

1a, 7a-19a

O R1

20a-24a

20b 49% [5 mol% CuTC]

HCl

NH2

R1

Et2O

R2 R3

1, 7-19 1 mmol scale

O

Scheme 2. Transition Metal-Catalyzed Aza-Rubottom Oxidation.

Me CO2Et

Br

21b 82% [1 mol% Rh2(esp)2] 40% [5 mol% CuTC]

22b 55% [1 mol% Rh2(esp)2] O

NH2 HCl CO2Et

N

Me Me NH2 2HCl

NH2 HCl CO2Et

F O

O NH2 HCl

NH2 HCl Me Me

7b: 65%

OMe O

O NH2 HCl MeO

Me Me

NH2

HCl

Ph Me NH2 HCl

Me

1b: 82%

O

O

8b: 65%

9b: 69%

O

O

NH2 HCl

Me NH2 HCl

NH2

S

Me Me

HCl

Me Me

F

11b: 57%

10b: 79%

12b: 56%

13b: 73%

O Me

N

O

Me NH2 HCl Me

Me NH2 HCl

N

14b: 54%

15b: 53%

16a: 55% 16b: 29%[b] Cl O

O Me

NH2 HCl Me

O Me

O

Me NH2

N

HCl

Me

Me NH2

HCl

O O

MeO

18b: 69%

17b: 54%

19b: 21% (78% brsm)

Substrates that failed to react OTBS CO2Et Me

20 (E/Z mixture)

OTBS Me

OTBS CO2Et Me

21 (E/Z mixture)

Br

N

24b 75% [1 mol% Rh2(esp)2]

[a] Reactions were conducted on a 1 mmol scale. HOSA (1.2 equiv), pyridine (2.4 equiv) were dissolved in 5 mL of HFIP. The silyl enol ether was added at room temperature with rigorous stirring, followed by the metal catalyst. The purified free amines were treated with a solution of HCl in diethyl ether to obtain the corresponding HCl salts. We hypothesized that in the case of less reactive silyl enol ethers, a more reactive nitrogen source is needed. Naturally, we decided to use transition metal catalysis, hoping that the more reactive metal-nitrenoid complexes can overcome the energy barrier and will aminate even these less electron-rich substrates.

Me NH2 HCl O

O

23b 73% [1 mol% Rh2(esp)2]

Me

22 (E/Z mixture)

[a] Reactions were conducted on a 1 mmol scale. DPH (1.2 equiv), diisopropylethylamine (1.5 equiv) were dissolved in 5 mL of HFIP. The silyl enol ether was added at room temperature with rigorous stirring. The purified free amines were treated with a solution of HCl in diethyl ether to obtain the corresponding HCl salts. [b] The free amine rapidly decomposes when concentrated. However, when more strongly electron-withdrawing substituents are present in the silyl enol ethers (20-22), the reactions failed to proceed. For example, an ester group is sufficient to suppress the amination of silyl enol ether via either the inductive effect (20) or conjugation (21). In the case of 22, we suspect the in-situ protonation of the pyridinyl nitrogen in HFIP (pKa ~ 9.3) severely reduced the reactivity of the silyl enol ether to prevent the reaction from taking place. We also found that the less stable silyl ketene acetals will undergo fast desilylation under the reaction conditions, which severe16 ly reduce the yield.

The reactions worked as predicted, and primary αaminoketones bearing electron-withdrawing substituents were obtained in good to excellent yields (Scheme 2). Both Cu- and Rh-complexes can catalyze this transformation, although Rh is significantly more efficient (Scheme 2, 21b). Silyl enol ethers with carboxylate substituents (Scheme 2, 23b and 24b) as well as electron-deficient heterocycles (Scheme 2, 22b) were successfully aminated with the addition of only 1 mol% Rh2(esp)2 catalyst, and the reaction reaches completion within 6 h at room temperature. It should be noted that very recently, Professor E. J. Corey and coworker reported a similar Rh-catalyzed reaction in the 17 context of the synthesis of ketamine analogues. Like the un-catalyzed reaction, the transition metalcatalyzed aza-Rubottom oxidation also requires the use of HFIP as the solvent for effective conversion. Moreover, the reaction becomes sluggish with the addition of a co-solvent. This echoes the significant rate acceleration effect by fluorinated solvents that we have observed in Rh-catalyzed NHaziridination of unactivated olefins. Intrigued by this observation, we decided to search the literature for some insights on the mechanism of this transformation. Although the consensus agrees that the rate acceleration by HFIP is most likely caused by hydrogen bond interactions,18 to the best of our knowledge no detailed mechanistic studies have been carried out on the effect of fluorinated solvents in olefin aziridination reactions. However, an outstanding study on the rate acceleration by HFIP in the context of olefin epoxidation was reported by the Berkessel group in 2006.19 In

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this study, it is reported that HFIP enables the epoxidation of olefins by hydrogen peroxide in the absence of additional catalysts. In the subsequent quantum-chemical investigation, Berkessel et. al. proposed that higher-order aggregates of HFIP molecules are responsible for the rate acceleration.

Scheme 3. Mechanistic Hypothesis. OTBS

TBSO R1

R2 R3

H

DPH HFIP

H

O

H

CF3

N O

O H F3C

L.K. gratefully acknowledges the generous financial support of Rice University, National Institutes of Health (R01 GM114609-04), National Science Foundation (CAREER:SusChEM CHE-1546097), the Robert A. Welch Foundation (Grant C1764), that are greatly appreciated. The authors also thank Professor E. J. Corey for helpful discussions.

R1

CF3

F3C

ACKNOWLEDGMENT

R3 R2

OTBS

O

R1 HN

R3 R2

O2N

R1

NH2 R2 R3

REFERENCES 1.

NO2

A similar mechanism is likely involved in the aza-Rubottom oxidation, in which higher-order solvent aggregates formed from multiple HFIP molecules activates the hydroxylaminederived aminating reagent via cooperative hydrogen-bonding interactions (Scheme 3). This explains the detrimental effect caused by a co-solvent, since it will exponentially affect the concentration of the active HFIP aggregates. An intriguing implication based on this hypothesis is that an enantioselective version of this reaction can be potentially achieved with a chiral nonracemic hydrogen-bond donor catalyst that activates achiral hydroxylamines. This could be analogous to what has been reported for asymmetric epoxi20 dation catalyzed by organocatalysts.

2.

3.

4.

In summary, we have developed two sets of conditions for the synthesis of primary α-aminoketones from silyl enol ethers. Electron-rich substrates can be α-aminated without transition metal catalysis, while substrates bearing electronwithdrawing substituents can undergo α-amination with the help of Rh or Cu catalysts. Solvent aggregates formed from multiple HFIP molecules are likely responsible for the observed reactivity. We hope these aza-Rubottom reactions will become valuble synthetic tools for organic synthesis.

ASSOCIATED CONTENT 5.

Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental details, characterizations of compounds and NMR spectra. (PDF)

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]

Notes The authors declare no competing financial interests. It should be noted that like many aromatic nitro compounds, DPH can potentially undergo highly energetic selfdecomposition when heated above 100 ºC in the presence of a strong base at high concentration. Although we have not observed any such incident, it is important to use all appropriate PPEs and safety precautions when carrying out reactions with DPH and avoid using strong base and/or temperature above 50 ºC.

6.

7.

(a) Erdik, E., Electrophilic α-amination of carbonyl compounds. Tetrahedron 2004, 60, 8747-8782; (b) Ciganek, E., Electrophilic amination of carbanions, enolates, and their surrogates. Organic Reactions (Hoboken, NJ, United States) 2008, 72, 1-366. Deng, Q. H.; Bleith, T.; Wadepohl, H.; Gade, L. H., Enantioselective iron-catalyzed azidation of beta-keto esters and oxindoles. J. Am. Chem. Soc. 2013, 135, 5356-5359. Zhang, Z. Q.; Chen, T.; Zhang, F. M., Copper-Assisted Direct Nitration of Cyclic Ketones with Ceric Ammonium Nitrate for the Synthesis of Tertiary alpha-Nitro-alpha-substituted Scaffolds. Org Lett 2017, 19, 1124-1127. (a) Momiyama, N.; Yamamoto, H., Enantioselective O- and NNitroso Aldol Synthesis of Tin Enolates. Isolation of Three BINAP−Silver Complexes and Their Role in Regio- and Enantioselectivity. J. Am. Chem. Soc. 2004, 126, 5360-5361; (b) Momiyama, N.; Yamamoto, H., Brønsted Acid Catalysis of Achiral Enamine for Regio- and Enantioselective Nitroso Aldol Synthesis. J. Am. Chem. Soc. 2005, 127, 1080-1081; (c) Sandoval, D.; Frazier, C. P.; Bugarin, A.; Read de Alaniz, J., Electrophilic αAmination Reaction of β-Ketoesters Using NHydroxycarbamates: Merging Aerobic Oxidation and Lewis Acid Catalysis. J. Am. Chem. Soc. 2012, 134, 18948-18951; (d) Xu, C.; Zhang, L.; Luo, S., Merging aerobic oxidation and enamine catalysis in the asymmetric alpha-amination of betaketocarbonyls using N-hydroxycarbamates as nitrogen sources. Angew. Chem. Int. Ed. 2014, 53, 4149-4153; (e) Sandoval, D.; Samoshin, A. V.; Read de Alaniz, J., Asymmetric Electrophilic alpha-Amination of Silyl Enol Ether Derivatives via the Nitrosocarbonyl Hetero-ene Reaction. Org. Lett. 2015, 17, 45144517. (a) Evans, D. A.; Nelson, S. G., Chiral Magnesium Bis(sulfonamide) Complexes as Catalysts for the Merged Enolization and Enantioselective Amination of NAcyloxazolidinones. A Catalytic Approach to the Synthesis of Arylglycines. J. Am. Chem. Soc. 1997, 119, 6452-6453; (b) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bøgevig, A.; Jørgensen, K. A., Direct l-Proline-Catalyzed Asymmetric αAmination of Ketones. J. Am. Chem. Soc. 2002, 124, 6254-6255; (c) Janey, J. M., Recent advances in catalytic, enantioselective alpha aminations and alpha oxygenations of carbonyl compounds. Angew. Chem. Int. Ed. 2005, 44, 4292-4300; (d) Marigo, M.; Jørgensen, K. A., Organocatalytic direct asymmetric αheteroatom functionalization of aldehydes and ketones. Chem. Commun. 2006, 2001-2011; (e) Yang, X.; Toste, F. D., Direct asymmetric amination of alpha-branched cyclic ketones catalyzed by a chiral phosphoric acid. J. Am. Chem. Soc. 2015, 137, 3205-3208. (a) Schlessinger, R. H.; Graves, D. D., A synthesis of the tetramic acid subunit of streptolydigin: A reactivity definition of this subunit as an Emmons reagent. Tetrahedron Lett. 1987, 28, 43854388; (b) Kendrick, D. A.; Kolb, M., A new, short synthetic route to α-substituted 5,5-difluoro-4-pentenoic acid esters. J. Fluorine Chem. 1989, 45, 265-272; (c) Smulik, J. A.; Vedejs, E., Improved Reagent for Electrophilic Amination of Stabilized Carbanions. Org. Lett. 2003, 5, 4187-4190. Mizar, P.; Wirth, T., Flexible stereoselective functionalizations of ketones through umpolung with hypervalent iodine reagents. Angew. Chem. Int. Ed. 2014, 53, 5993-5997.

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Journal of the American Chemical Society 8. (a) Zhao, B.; Du, H.; Shi, Y., A Cu(I)-Catalyzed C−H α-Amination of Esters. Direct Synthesis of Hydantoins. J. Am. Chem. Soc. 2008, 130, 7220-7221; (b) Evans, R. W.; Zbieg, J. R.; Zhu, S.; Li, W.; MacMillan, D. W., Simple catalytic mechanism for the direct coupling of alpha-carbonyls with functionalized amines: a onestep synthesis of Plavix. J. Am. Chem. Soc. 2013, 135, 16074-16077; (c) Fisher, D. J.; Burnett, G. L.; Velasco, R.; Read de Alaniz, J., Synthesis of Hindered alpha-Amino Carbonyls: CopperCatalyzed Radical Addition with Nitroso Compounds. J. Am. Chem. Soc. 2015, 137, 11614-11617; (d) Tokumasu, K.; Yazaki, R.; Ohshima, T., Direct Catalytic Chemoselective alpha-Amination of Acylpyrazoles: A Concise Route to Unnatural alpha-Amino Acid Derivatives. J. Am. Chem. Soc. 2016, 138, 2664-2669. 9. (a) Davis, F. A.; Chen, B. C., Asymmetric hydroxylation of enolates with N-sulfonyloxaziridines. Chem. Rev. 1992, 92, 919934; (b) Williamson, K. S.; Michaelis, D. J.; Yoon, T. P., Advances in the Chemistry of Oxaziridines. Chem. Rev. 2014, 114, 80168036. 10. (a) Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R., Peracid oxidation of trimethylsilyl enol ethers: A facile α-hydroxylation procedure. Tetrahedron Lett. 1974, 15, 4319-4322; (b) Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek, E., α-Hydroxylation of enolates and silyl enol ethers. Org. React. 2003, 62, 1-356. 11. Nicolaou, K. C.; Chen, P.; Zhu, S.; Cai, Q.; Erande, R. D.; Li, R.; Sun, H.; Pulukuri, K. K.; Rigol, S.; Aujay, M.; Sandoval, J.; Gavrilyuk, J., Streamlined Total Synthesis of Trioxacarcins and Its Application to the Design, Synthesis, and Biological Evaluation of Analogues Thereof. Discovery of Simpler Designed and Potent Trioxacarcin Analogues. J. Am. Chem. Soc. 2017, 139, 15467-15478. 12. An early example of this type of reactivity was reported by the Evans group in which an N-tosyl aminoketone was obtained from an N-tosyl aziridine synthesized via a copper-catalyzed reaction: (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T., Coppercatalyzed aziridination of olefins by (N-(ptoluenesulfonyl)imino)phenyliodinane. J. Org. Chem. 1991, 56, 6744-6746; (b) Evans, D. A.; Bilodeau, M. T.; Faul, M. M., Development of the Copper-Catalyzed Olefin Aziridination Reaction. J. Am. Chem. Soc. 1994, 116, 2742-2753. 13. Rh is also known to facilitate this transformation via N-tosyl aziridination, see: Tanaka, M.; Kurosaki, Y.; Washio, T.; Anada, M.; Hashimoto, S., Enantioselective amination of silylketene acetals with (N-arylsulfonylimino)phenyliodinanes catalyzed by chiral dirhodium(II) carboxylates: asymmetric synthesis of phenylglycine derivatives. Tetrahedron Lett. 2007, 48, 8799-8802. 14. (a) Jat, J. L.; Paudyal, M. P.; Gao, H.; Xu, Q. L.; Yousufuddin, M.; Devarajan, D.; Ess, D. H.; Kürti, L.; Falck, J. R., Direct stereospecific synthesis of unprotected N-H and N-Me aziridines from olefins. Science 2014, 343, 61-65; (b) Ma, Z.; Zhou, Z.; Kürti, L., Direct and Stereospecific Synthesis of N-H and N-Alkyl Aziridines from Unactivated Olefins Using Hydroxylamine-OSulfonic Acids. Angew. Chem. Int. Ed. 2017, 56, 9886-9890. 15. N-tosyl aziridination of silyl enol ethers can take place under photochemical conditions in the absence of transition metal catalysis: (a) Kobayashi, Y.; Masakado, S.; Takemoto, Y., Photoactivated N-Acyliminoiodinanes Applied to Amination: an ortho-Methoxymethyl Group Stabilizes Reactive Precursors. Angew. Chem. Int. Ed. 2018, 57, 693-697; (b) Masakado, S.; Kobayashi, Y.; Takemoto, Y., Photo-Induced Aziridination of Alkenes with N-Sulfonyliminoiodinanes. Chem. Pharm. Bull. (Tokyo). 2018, 66, 688-690. 16. Copper-catalyzed amination of tri-substituted silyl ketene acetals has been previously reported in the literature, although the amino groups are fully substituted (i.e. tertiary amino group): (a) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M., Copper-catalyzed amination of ketene silyl acetals with hydroxylamines: electrophilic amination approach to alpha-amino acids. Angew. Chem. Int. Ed. 2012, 51, 11827-11831; (b) Miura, T.; Morimoto, M.; Murakami, M., Copper-Catalyzed Amination of Silyl Ketene Acetals with N-Chloroamines. Org. Lett. 2012, 14, 5214-5217.

17. Han, Y.; Corey, E. J., Method for the Direct Enantioselective Synthesis of Chiral Primary α-Amino Ketones by Catalytic αAmination. Org. Lett. 2019, 21, 283-286. 18. Colomer, I.; Chamberlain, A. E. R.; Haughey, M. B.; Donohoe, T. J., Hexafluoroisopropanol as a highly versatile solvent. Nature Reviews Chemistry 2017, 1, 0088. 19. Berkessel, A.; Adrio, J. A., Dramatic Acceleration of Olefin Epoxidation in Fluorinated Alcohols:  Activation of Hydrogen Peroxide by Multiple H-Bond Networks. J. Am. Chem. Soc. 2006, 128, 13412-13420. 20. (a) Lifchits, O.; Reisinger, C. M.; List, B., Catalytic Asymmetric Epoxidation of α-Branched Enals. J. Am. Chem. Soc. 2010, 132, 10227-10229; (b) Lifchits, O.; Mahlau, M.; Reisinger, C. M.; Lee, A.; Farès, C.; Polyak, I.; Gopakumar, G.; Thiel, W.; List, B., The Cinchona Primary Amine-Catalyzed Asymmetric Epoxidation and Hydroperoxidation of α,β-Unsaturated Carbonyl Compounds with Hydrogen Peroxide. J. Am. Chem. Soc. 2013, 135, 6677-6693; (c) Zhu, Y.; Wang, Q.; Cornwall, R. G.; Shi, Y., Organocatalytic asymmetric epoxidation and aziridination of olefins and their synthetic applications. Chem. Rev. 2014, 114, 8199-8256.

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