Abstract
We report a general protocol for γ-C(sp3)–H acyloxylation and alkoxylation of free amines using 2-hydroxynicotinaldehyde as the transient directing group. In the presence of an electrophilic fluorinating bystanding oxidant and acetic acid, a wide range of aliphatic amines could be oxygenated selectively at the γ-methyl positions. A vast variety of aryl, heteroaryl, and aliphatic acids could also be successfully coupled under this C–O bond formation reaction to afford amine containing esters. Switching the nucleophile from acids to alcohols enables alkoxylation of free amines. Importantly, natural products and drug molecules such as ibuprofen, isozepac, fenbufen, and lithocholic acid are all compatible coupling partners. Notably, synthesis of these mono-protected amino alcohols from free amino alcohols using conventional selective protection are not always feasible.
Keywords: Transient Directing Group, C(sp3)–H Activation, Palladium, C(sp3)–H Oxygenation, Bystanding Oxidant, Amine
Graphical Abstract
One of the major challenges in directed C–H activation is to enable the use of native substrates without covalently installing external directing groups. While the combination of weak coordination from substrates and ligand acceleration has been successful in enabling a wide range of C–H activation reactions of free carboxylic acids and Weinreb amides,1 the development of catalytic transient directing groups (TDGs) for aliphatic aldehydes, ketones, and free amines has emerged as a complementary approach.2–5 While most of these reactions are limited to (hetero)arylations,3–5 efforts to develop other C–X, and C–O bond forming reactions have recently afforded new advances.6 Using an electrophilic [F+] reagent as either the bystanding oxidant or the fluorinating agent, we have recently developed selective C–O and C–F bond formation reactions of 2-alkylbenzaldehydes via a novel amino amide transient directing group (Scheme 1).6a Inspired by this development, we have subsequently developed the first example of TDG enabled γ-C(sp3)–H fluorination of free amines using similar [F+] reagents (Scheme 2).6b Based on this particular investigation and our previous studies of using [F+] as bystanding oxidant for making C–C, C–N or C–O bonds,7 we decided to explore the possibility of γ-oxidation of free amines using transient directing groups.
Scheme 1.
TDG Enabled Acetoxylation of 2-Alkylbenzaldehydes
Scheme 2.
Pyridone Assisted γ-C(sp3)–H Fluorination of Free Amines
Considering the synthetic utility, we began to develop γ-acyloxylation with carboxylic acids and γ-etherification with alcohols which could afford of mono-protected amino alcohols that are not trivial to make. Although γ-C(sp3)–H acetoxylation of amines have been reported before, most of these reactions require the installation of exogenous directing groups.8–9 A single example of free amine directed γ-C(sp3)–H acetoxylation is limited to amines containing α-quaternary centers (Scheme 3).10 Herein, we report a transient directing group strategy for γ-C(sp3)–H oxygenation of broad range of free amines using N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate as the bystanding oxidant (Scheme 4). Advantageous to traditional γ-amino alcohol derivative synthesis which requires protection and deprotection of the amino group, our protocol features a one-step coupling between a wide range of aliphatic amines and a vast variety of acids and alcohols via selective C–O bond formation at the unactivated γ positions.
Scheme 3.
Free Amine Directed γ-C(sp3)–H Acetoxylation
Scheme 4.
This Work: TDG Enabled γ-C(sp3)–H Acylocylation and Alkoxylation of Free Amines
We began our experimental efforts by testing γ-acetoxylation of sec-butylamine (Table 1). Under similar reaction conditions as our previous γ-methyl fluorination conditions in a 19:1 mixture HFIP and AcOH,6b we were pleased to find the desired acetoxylated product in 68% NMR yield when N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate was used as the [F+] bystanding oxidant and 2-hydroxylnicotinaldehyde as the TDG (Table 1, entry 1). Only less than 10% of the product was detected in the absence of TDG, thus demonstrating the importance of TDG in this acetoxylation reaction. (entry 2). Since we had already established moderate reactivity with pyridinium salt, we wondered whether other cheaper and more accessible oxidants could also promote this reaction. When we changed the oxidant to PhI(OAc)2 the yield lowered to only 17% (entry 3). Upon evaluation of various peroxide-based oxidants, we discovered that although H2O2 and AcOOtBu gave inferior yields of the product in 15% and 21% respectively (entry 4–5), TBHP was an effective oxidant for this reaction, providing the product in 53% yield (entry 6). K2S2O8 was also identified as another potentially effective oxidant for this reaction (entry 7). Unfortunately, despite extensive reaction optimization, the reaction could only be improved to around 70% yield using TBHP or K2S2O8 as the oxidant (entry 8–9). Gratifyingly, the reaction could be further optimized to above 90% isolated yield by increasing the loading of the TDG with 2.0 eq. of N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (entry 10–12).
Table 1.
 | |||
|---|---|---|---|
| Entry | Oxidants | Reaction Conditions | Yield (%) |
| 1 | 1.50 eq. N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate | 20 mol% TDG, HFIP:AcOH (19:1) | 68 (63c) |
| 2 | 1.50 eq. N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate | No TDG, HFIP:AcOH (19:1) | <10 |
| 3 | 1.50 eq. Phl(OAc)2 | 20 mol% TDG, HFIP:AcOH (19:1) | 17 |
| 4 | 1.50 eq. H202 | 20 mol% TDG, HFIP:AcOH (19:1) | 15 |
| 5 | 1.50 eq. AcOOtBu | 20 mol% TDG, HFIP:AcOH (19:1) | 21 |
| 6 | 1.50 eq. TBHP (5M in decane) | 20 mol% TDG, HFIP:AcOH (19:1) | 53 |
| 7 | 1.50 eq. K2S2Oe | 20 mol% TDG, HFIP:AcOH (19:1) | 36 |
| 8 | 2.0 eq. TBHP (5M in decane) | 50 mol% TDG, HFIP:AcOH (19:1) | 68 (67)c |
| 9 | 2.0 eq. K2S2Oe + 10 mol% (nBu)4NOAc | 30 mol% TDG, HFIP:AcOH (2:1) | 66 |
| 10 | 2.0 eq. N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate | 30 mol% TDG, HFIP:AcOH (19:1) | 89 |
| 11 | 2.0 eq. N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate | 30 mol% TDG, HFIP:AcOH (2:1) | 89 |
| 12 | 2.0 eq. N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate | 50 mol% TDG, HFIP:AcOH (19:1) | 94 (91)c |
Experiments were performed with substrate 1a (0.10 mmol), Pd(OAc)2 (0.01 mmol), TDG, oxidants, HFIP:AcOH (0.5 mL), 70 °C, 12 h.
Yields were determined by 1H NMR analysis of the crude product using 1,1,2,2-tetrachloroethane as the internal standard.
Isolated yields.
With the optimized conditions in hand, we next investigated the amine scope of this acetoxylation reaction (Table 2). For ease of analysis and separation, the acetoxylated products were isolated in the form of the Bz-protected amines. While sec-butylamine could be acetoxylated in 91% isolated yield (2a), the yield lowered to 44% when 3-aminohexane was employed as the substrate (2b). For 3-aminopentane, the di-acetoxylated product was obtained as the sole product in 42% yield (2c). Various oxygen containing substrates could also be acetoxylated in moderate yields (2d-f). Simple aliphatic amines without α-alkyl substituents such as 2-methylbutylamine, isobutylamine and even propylamine were also compatible substrates for this reaction, affording the corresponding products in 30–70% yields (2g-i). Acetoxylation of trans-2-methyl-cyclohexylamine could afford the product in 22% yield, whereas the cis isomer was completely unreactive (2j). Since AcOH was a good oxygen source for this protocol, we wondered whether other acids could also be coupled similarly for this reaction. We were pleased to find that γ-C(sp3)–H oxygenation of 1a with a vast variety of aryl acids proceeded smoothly with good to excellent yields (Table 3). Notably, no acetoxylation product was observed in the presence of a different carboxylic acid without AcOH in pure HFIP. Various benzoic acids containing para and meta substituents, including methyl, methoxy, trifluoromethyl, nitro, cyano, and halogens, were well tolerated regardless of their electronic properties (2a1–9). Ortho-substituted benzoic acids containing iodo or phenyl groups provided the corresponding products in good to excellent yields (2a10–12). Sterically demanding substrates such as 2,6-dimethoxy, 2-bromo-6-methyl, and even2,4,6-triisopropyl benzoic acids were also well tolerated (2a13–15). Importantly, heteroaryl acids containing pyridines with different substitutions such as fluoro- and trifluoromethyl groups are all compatible coupling partners, providing 50–82% yields (2a16–20). Coupling with other heteroaryl acids containing thiophene, furan, chromene, and even pyrazole groups were successfully accomplished with this protocol (2a21–25). Notably, higher TDG loadings are used for certain heteroaryl acids presumably to prevent catalyst poisoning by the heteroaryl acids.
Table 2.
|
Experiments were performed with substrate 1a (0.10 mmol), Pd(OAc)2 (0.01 mmol), TDG (0.05 mmol), N-fluoro 2,4,6-methylpyridinium tetrafluoroborate (0.20 mmol), HFIP:AcOH (19:1) (0.5 mL), 70 °C, 16 h.
Isolated yields.
Reaction performed with 0.75 eq of TDG.
Table 3.
|
Experiments were performed with substrate 1a (0.10 mmol), Pd(OAc)2 (0.01 mmol), TDG (0.05 mmol), N-fluoro 2,4,6-methylpyridinium tetrafluoroborate (0.20 mmol), HFIP (0.5 mL), 70 °C, 16 h.
Isolated yields.
Reaction performed with 0.75 eq of TDG.
The scope of various aliphatic acids was investigated next (Table 4). Primary aliphatic acid such as 2-norbornaneacetic acid afforded the corresponding ester product in 67% isolated yield (2a26). Secondary aliphatic acids containing oxygenated functionalities and unsaturation were also tolerated in moderate yields (2a27–29). Sterically demanding tertiary acids containing tert-butyl, phenyl, and adamantyl groups were all coupled successfully in 60–68% islolated yields (2a30–32). Aliphatic acids from natural products such as ketopinic acid and camphanic acid afforded the corresponding products in 51% and 81% respectively (2a33–34). Lastly, N-protected amino acids could also be coupled under this protocol in good efficiencies (2a35–36).
Table 4.
|
Experiments were performed with substrate 1a (0.10 mmol), Pd(OAc)2 (0.01 mmol), TDG (0.075 mmol), N-fluoro 2,4,6-methylpyridinium tetrafluoroborate (0.20 mmol), HFIP (0.5 mL), 70 °C, 16 h.
Isolated yields.
Reaction performed with 0.5 eq of TDG.
Reaction performed with 2.0 eq of acid.
Reaction performed with 1.0 eq of TDG.
Since the reaction was compatible with a vast range of different carboxylic acids, we next wondered whether other oxygen containing nucleophiles such as alcohols could also serve as effective coupling partners for this reaction. We were pleased to find that γ-C(sp3)–H oxygenation of 1a with a range of aliphatic alcohols could also be accomplished, albeit in lower efficiencies (Table 5). Primary alcohols such as methanol, ethanol, cyclobutylmethanol, cyclopentylmethanol, cyclohexylmethanol, and benzyl alcohol all underwent the desired alkoxylation reaction in 37–65% yields (2a37–42). Secondary alcohols such as isopropanol, cyclobutanol, cyclopentanol, cyclohexanol, cycloheptanol, and even 2-adamantanol were also effective nucleophiles, affording the hindered ethers in 40–55% isolated yields (2a43–48). Remarkably, even tertiary alcohols such as tBuOH, and 1-adamantanol were competent nucleophiles to afford the highly hindered ethers in 23% and 18% isolated yields respectively with the aid of an electron-deficient pyridone ligand (2a49–50). The ability to perform C–H oxygenation with secondary and tertiary alcohols provides a straight-forward method for the synthesis of hindered aminoethers, which is difficult to achieve via conventional approaches. Furthermore, we have also evaluated other less reactive amines (1c-d, 1g-h, 1i) with methanol as the coupling partner. The NMR yields of 1c and 1d were similar to that of the model substrate 1a. Roughly 40% NMR yield of the alkoxylated product was detected for 1g and 1h. Simple propylamine (1i) with methanol only gave 10–15% NMR yields.
Table 5.
|
Experiments were performed with substrate 1a (0.10 mmol), Pd(OAc) (0.01 mmol), TDG (0.1 mmol), N-fluoro 2,4,6-methylpyridinium tetrafluoroborate (0.20 mmol), HFIP:ROH (19:1) (0.5 mL), 70 °C, 16 h.
Isolated yields.
Reaction performed with 0.75 eq TDG (0.075 mmol) and 0.5 eq of 5-chloro-3-nitropyridin-2-ol as the pyridone ligand.
Reaction performed with 0.5 eq of TDG.
Reaction performed with 1.0 eq TDG (0.1 mmol) and 0.5 eq of 5-chloro-3-nitropyridin-2-ol as the pyridone ligand.
To demonstrate the synthetic utility of this γ-C(sp3)–H oxygenation reaction, we were pleased to find that the catalyst and TDG loading could be lowered to 2 mol% and 20 mol% respectively, thus rendering our protocol highly efficient (Scheme 5). In addition, the C–H oxygenated free amine product could also be isolated in 78% yield. More importantly, natural products and drug molecules such as ibuprofen, isozepac, fenbufen, and lithocholic acid were all well tolerated (Table 6), thus demonstrating this protocol’s potential to perform late-stage functionalization and provide facile access to amine containing drug analogs.
Scheme 5.
Catalyst Loading and Synthetic Applications
Table 6.
|
Experiments were performed with substrate 1a (0.10 mmol), Pd(OAc)2 (0.01 mmol), TDG (0.075 mmol), N-fluoro 2,4,6-methylpyridinium tetrafluoroborate (0.20 mmol), HFIP (0.5 mL), 70 °C, 16 h.
Isolated yields.
In summary, we have developed a general method for γ-C(sp3)–H oxygenation of free aliphatic amines using 2-hydroxynicotinaldehyde as the transient directing group and N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate as the [F+] bystanding oxidant. This reaction features a wide amine scope with good functional group tolerance. A vast range of aryl, heteroaryl, and aliphatic acids, as well as primary, secondary, and even tertiary alcohols are all compatible nucleophiles in this γ-C(sp3)–H oxygenation reaction. Compared to traditional γ-amino alcohol derivative synthesis which require protection and deprotection of the amino group, our reaction provides facile access to these compounds and even hindered ethers in a single step. More importantly, natural products and drug molecules are also competent coupling partners, thus demonstrating this protocol’s potential for late-stage functionalization to access amine containing drug analogs. Efforts in designing new TDG and ligands to enable coupling of other nucleophiles are currently underway in light of these developments.
Supplementary Material
ACKNOWLEDGMENT
We gratefully acknowledge The Scripps Research Institute, the NIH (NIGMS 5R01 GM084019), and Bristol-Myers Squibb for financial support. Y-Q. C. thanks the NSF Graduate Research Fellowships for financial support. Dr. Jason Chen, Emily Strugell and Brittany Sanchez from the Scripps Automated Synthesis Center are acknowledged for guidance on analytical methods and DoE screening.
Footnotes
Supporting Information. Experimental procedures and spectral data for all new compounds and full computational data (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.
REFERENCES
- (1).a) Giri R; Maugel N; Li J-J; Wang D-H; Breazzano SP; Saunder LB; Yu J-Q Palladium-Catalyzed Methylation and Arylation of sp2 and sp3 C–H Bonds in Simple Carboxylic Acids. J. Am. Chem. Soc 2007, 129, 3510–3511. [DOI] [PubMed] [Google Scholar]; b) Chen G; Zhuang Z; Li G-C; Saint-Denis TG; Xiao Y; Joe CL; Yu J-Q Ligand-Enabled β-C–H Arylation of α-Amino Acids Without Installing Exogenous Directing Groups. Angew. Chem., Int. Ed 2017, 56, 1506–1509. [DOI] [PMC free article] [PubMed] [Google Scholar]; c) Zhu Y; Chen X; Yuan C; Li G; Zhang J; Zhao Y Pd-catalysed ligand-enabled carboxylate-directed highly regioselective arylation of aliphatic acids. Nat. Commun 2017, 8, 14904. [DOI] [PMC free article] [PubMed] [Google Scholar]; d) Ghosh KK; van Gemmeren M Pd-Catalyzed β-C(sp3)–H Arylation of Propionic Acid and Related Aliphatic Acids. Chem. Eur. J 2017, 23, 17697–17700. [DOI] [PubMed] [Google Scholar]; e) Zhuang Z; Yu C; Chen G; Wu Q; Hsiao Y; Joe CL; Qiao JX; Poss MA; Yu J-Q Ligand-Enabled β-C(sp3)−H Olefination of Free Carboxylic Acids. J. Am. Chem. Soc 2018, 140, 10363–10367. [DOI] [PMC free article] [PubMed] [Google Scholar]; f) Uttry A; Gemmeren M. Van. The Direct Pd-Catalyzed β-C(sp3)−H Activation of Carboxylic Acids. Synlett. 2018, 29, 1937–1943. [Google Scholar]; g) Park H; Chekshin N; Shen P; Yu J-Q Ligand-Enabled, Palladium-Catalyzed β-C(sp3)–H Arylation of Weinreb Amides. ACS Catal 2018, 8, 9292–9297. [DOI] [PMC free article] [PubMed] [Google Scholar]; h) Ghosh KK; Uttry A; Koldemir A; Ong M; Gemmeren M. Van. Direct β-C(sp3)–H Acetoxylation of Aliphatic Carboxylic Acids. Org. Lett 2019, 21, 7154–7157. [DOI] [PubMed] [Google Scholar]; i) Dolui P; Das J; Chandrashekar HB; Anjana SS; Maiti D Ligand-Enabled PdII-Catalyzed Iterative γ-C(sp3)–H Arylation of Free Aliphatic Acid. Angew. Chem. Int. Ed 2019, 58, 13773–13777. [DOI] [PubMed] [Google Scholar]; j) Liu L; Liu Y; Shi B Synthesis of Amino Acids and Peptides with Bulky Side Chains via Ligand-Enabled Carboxylate-Directed γ-C(sp3)–H Arylation. Chem. Sci 2020, 11, 290–294. [DOI] [PMC free article] [PubMed] [Google Scholar]; k) Zhuang Z; Yu J-Q Lactonization as a General Route to β-C(sp3)–H Functionalization. Nature 2020, 577, 656–659. [DOI] [PMC free article] [PubMed] [Google Scholar]
- (2).For selected reviews on transient directing groups:; a) Zhao Q; Poisson T; Pannecoucke X; Basset T The Transient Directing Group Strategy: A New Trend in Transition-Metal-Catalyzed C–H Bond Functionalization. Synthesis. 2017, 49, 4808–4826. [Google Scholar]; b) Gandeepan P; Ackermann L Transient Directing Groups for Transformative C–H Activation by Synergistic Metal Catalysis. Chem. 2018, 4, 199–222. [Google Scholar]; c) St John-Campbell S; Bull JA Transient imines as ‘next generation’ directing groups for the catalytic functionalisation of C–H bonds in a single operation. Org. Biomol. Chem 2018, 16, 4582–4595. [DOI] [PubMed] [Google Scholar]; d) Rasheed OK; Sun B Advances in Development of C–H Activation/Functionalization Using a Catalytic Directing Group. ChemistrySelect. 2018, 3, 5689–5708. [Google Scholar]; e) Niu B; Yang K; Lawrence B; Ge H Transient Ligand-Enabled Transition Metal-Catalyzed C-H Functionalization. ChemSusChem. 2019, 12, 2955–2969. [DOI] [PubMed] [Google Scholar]
- (3).For examples on TDG enabled C(sp3)−H (hetero)arylations on Aldehydes:; a) Zhang F-L; Hong K; Li T-J; Park H; Yu J-Q Functionalization of C(sp3)–H bonds using a transient directing group. Science. 2016, 351, 252–256. [DOI] [PMC free article] [PubMed] [Google Scholar]; b) Yang K; Li Q; Liu Y; Li G; Ge H Catalytic C–H Arylation of Aliphatic Aldehydes Enabled by a Transient Ligand. J. Am. Chem. Soc 2016, 138, 12775–12778. [DOI] [PubMed] [Google Scholar]; c) Ma F; Lei M; Hu L Acetohydrazone: A Transient Directing Group for Arylation of Unactivated C(sp3)–H Bonds. Org. Lett 2016, 18, 2708–2711. [DOI] [PubMed] [Google Scholar]; d) St J-CS; White AJP; Bull JA Single operation palladium catalysed C(sp3)–H functionalisation of tertiary aldehydes: investigations into transient imine directing groups. Chem. Sci 2017, 8, 4840–4847. [DOI] [PMC free article] [PubMed] [Google Scholar]; e) Gou B; Liu H; Chen J; Zhou L Palladium-Catalyzed Site-Selective C(sp3)–H Arylation of Phenylacetaldehydes. Org. Lett 2019, 21, 7084–7088. [DOI] [PubMed] [Google Scholar]; f) Li B; Lawrence B; Li G; Ge H Ligand-Controlled Direct γ-C-H Arylation of Aldehydes. Angew. Chem. Int. Ed 2020, 59, 3078–3082. [DOI] [PubMed] [Google Scholar]; g) Wen F; Li Z Semicarbazide : A Transient Directing Group for C(sp3)-H Arylation of 2-Methylbenzaldehydes. Adv. Synth. Catal 2020, 362, 133–138. [Google Scholar]
- (4).For examples on TDG enabled C(sp3)−H (hetero)arylations on Ketones:; a) Hong K; Park H; Yu J-Q Methylene C(sp3)–H Arylation of Aliphatic Ketones Using a Transient Directing Group. ACS Catal. 2017, 7, 6938–6941. [DOI] [PMC free article] [PubMed] [Google Scholar]; b) Wang J; Dong C; Wu L; Xu M; Lin J; Wei K Palladium-Catalyzed β-C–H Arylation of Ketones Using Amino Amide as a Transient Directing Group: Applications to Synthesis of Phenanthridinone Alkaloids. Adv. Synth. Catal 2018, 360, 3709–3715. [Google Scholar]; c) Dong C; Wu L; Yao J; Wei K Palladium-Catalyzed β-C–H Arylation of Aliphatic Aldehydes and Ketones Using Amino Amide as a Transient Directing Group. Org. Lett 2019, 21, 2085–2089. [DOI] [PubMed] [Google Scholar]
- (5).For examples on TDG enabled C(sp3)−H (hetero)arylations on Amines:; a) Wu Y; Chen Y-Q; Liu T; Eastgate MD; Yu J-Q Pd-Catalyzed γ-C(sp3)–H Arylation of Free Amines Using a Transient Directing Group. J. Am. Chem. Soc 2016, 138, 14554–14557. [DOI] [PMC free article] [PubMed] [Google Scholar]; δ-C(sp3)−H arylation of 2-tert-butylaniline was demonstrated:; b) Xu Y; Young MC; Wang C; Magness DM; Dong G Catalytic C(sp3)−H Arylation of Free Primary Amines with an exo Directing Group Generated In Situ. Angew. Chem. Int. Ed 2016, 55, 9084–9087. [DOI] [PubMed] [Google Scholar]; c) Liu Y; Ge H Site-selective C–H arylation of primary aliphatic amines enabled by a catalytic transient directing group. Nat. Chem 2017, 9, 26–32. [Google Scholar]; d) Yada A; Liao W; Sato Y; Murakami M Buttressing Salicylaldehydes: A Multipurpose Directing Group for C(sp3)−H Bond Activation. Angew. Chem. Int. Ed 2017, 56, 1073–1076. [DOI] [PubMed] [Google Scholar]; e) St John-Campbell S; Ou AK; Bull JA Palladium-Catalyzed C(sp3)−H Arylation of Primary Amines Using a Catalytic Alkyl Acetal to Form a Transient Directing Group. Chem. Eur. J 2018, 24, 17838–17843. [DOI] [PMC free article] [PubMed] [Google Scholar]; f) Lin H; Wang C; Bannister TD; Kamenecka TM Site-Selective γ-C(sp3)−H and γ-C(sp2)−H Arylation of Free Amino Esters Promoted by a Catalytic Transient Directing Group. Chem. Eur. J 2018, 24, 9535–9541. [DOI] [PubMed] [Google Scholar]; g) Kapoor M; Liu D; Young MC Carbon Dioxide-Mediated C(sp3)-H Arylation of Amine Substrates. J. Am. Chem. Soc 2018, 140, 6818–6822. [DOI] [PubMed] [Google Scholar]
- (6).a) Park H; Verma P; Hong K; Yu J-Q Controlling Pd(IV) Reductive Elimination Pathways Enables Pd(II)-Catalysed Enantioselective C(sp3)-H Fluorination. Nat. Chem 2018, 10, 755–762. [DOI] [PMC free article] [PubMed] [Google Scholar]; b) Chen Y-Q; Singh S; Wu Y; Wang Z; Qiao J; Sunoj R; Yu J-Q Pd-catalyzed γ-C(sp3)–H Fluorination of Free Amines. J. Am. Chem. Soc 2020, under revision. [DOI] [PMC free article] [PubMed] [Google Scholar]
- (7).a) Engle KM; Mei T-S; Wang X; Yu J-Q Bystanding F+ Oxidants Enable Selective Reductive Elimination from High-Valent Metal Centers in Catalysis. Angew. Chem. Int. Ed 2011, 50, 1478–1491. [DOI] [PMC free article] [PubMed] [Google Scholar]; b) Mei T; Wang X; Yu J-Q Pd (II)-Catalyzed Amination of C-H Bonds Using Single-Electron or Two-Electron Oxidants. J. Am. Chem. Soc 2009, 131, 10806–10807. [DOI] [PubMed] [Google Scholar]; c) Wang X; Lu Y; Dai H; Yu J-Q Pd(II)-Catalyzed Hydroxyl-Directed C-H Activation / C-O Cyclization: Expedient Construction of Dihydrobenzofurans. J. Am. Chem. Soc 2010, 132, 12203–12205. [DOI] [PubMed] [Google Scholar]; d) Cheng X-F; Li Y; Su Y-M; Yin F; Wang J-Y; Sheng J; Vora HU; Wang X-S; Yu J-Q Pd(II)-Catalyzed Enantioselective C − H Activation/C − O Bond Formation: Synthesis of Chiral Benzofuranones. J. Am. Chem. Soc 2013, 135, 1236–1239. [DOI] [PMC free article] [PubMed] [Google Scholar]
- (8).a) Ye X; He Z; Ahmed T; Weise K; Akhmedov NG; Petersen JL; Shi X 1,2,3-Triazoles as Versatile Directing Group for Selective sp2 and sp3 C–H Activation: Cyclization vs Substitution. Chem. Sci 2013, 9, 3712–3716. [Google Scholar]; b) Cheng T; Yin W; Zhang Y; Zhang Y; Huang Y Palladium Catalyzed Acetoxylation of Benzylic C–H Bonds Using a Bidentate Picolinamide Directing Group. Org. Biomol. Chem 2014, 12, 1405–1411. [DOI] [PubMed] [Google Scholar]; c) Li Q; Zhang S; He G; Nack WA; Chen G Palladium-Catalyzed Picolinamide-Directed Acetoxylation of Unactivated γ-C(sp3)-H Bonds of Alkylamines. Adv. Synth. Catal 2014, 356, 1544–1548. [Google Scholar]; d) Liu P; Han J; Chen CP; Shi DQ; Zhao YS Palladium-Catalyzed Oxygenation of C(sp2)–H and C(sp3)–H Bonds under the Assistance of Oxalyl Amide. RSC Adv. 2015, 5, 28430–28434. [Google Scholar]; e) Pasunooti KK; Yang R; Banerjee B; Yap T; Liu C 5-Methylisoxazole-3-Carboxamide-Directed Palladium-Catalyzed γ-C(sp3)−H Acetoxylation and Application to the Synthesis of γ-Mercapto Amino Acids for Native Chemical Ligation. Org. Lett 2016, 18, 2696–2699. [DOI] [PubMed] [Google Scholar]; f) Zheng Y; Song W; Zhu Y; Wei B; Xuan L Pd-Catalyzed Acetoxylation of γ-C(sp3)−H Bonds of Amines Directed by a Removable Bts-Protecting Group. J. Org. Chem 2018, 83, 2448–2454. [DOI] [PubMed] [Google Scholar]; g) Jia W; Fernández-Ibáñez MÁ Ligand-Enabled γ-C(sp3)–H Acetoxylation of Triflyl-Protected Amines. Eur. J. Org. Chem 2018, 6088–6091. [Google Scholar]
- (9).a) Calleja J; Pla D; Gorman TW; Domingo V; Haffemayer B; Gaunt MJ A Steric Tethering Approach Enables Palladium-Catalysed C–H Activation of Primary Amino Alcohols. Nat. Chem 2015, 7, 1009–1061. [DOI] [PubMed] [Google Scholar]; b) Buettner CS; Willcox D; Chappell BGN; Gaunt MJ Mechanistic Investigation into the C(sp3)–H Acetoxylation of Morpholinones. Chem. Sci 2019, 10, 83–89. [DOI] [PMC free article] [PubMed] [Google Scholar]
- (10).Chen K; Wang D; Li Z-W; Liu Z; Pan F; Zhang Y-F; Shi Z-J Palladium Catalyzed C(sp3)–H Acetoxylation of Aliphatic Primary Amines to γ-amino Alcohol Derivatives Org. Chem. Front 2017, 4, 2097–2101. [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.