Palladium-Catalyzed β-C(sp3)–H Bond Arylation of Tertiary Aldehydes Facilitated by 2-Pyridone Ligands

2-Pyridone ligand-facilitated palladium-catalyzed direct C–H bond functionalization via the transient directing group strategy has become an attractive topic. Here, we report a Pd-catalyzed direct β-C(sp3)–H arylation reaction of tertiary aliphatic aldehydes by using an α-amino acid as a transient directing group in combination with a 2-pyridone ligand.


Introduction
Aliphatic aldehydes are not only important intermediates in chemical synthesis, but also ubiquitous structural units in pharmaceuticals and natural products [1][2][3].Among various synthetic approaches for aliphatic aldehydes, transition metal-catalyzed C-H bond functionalization represents one of the most efficient tools for the construction and derivatization of aliphatic aldehydes [4][5][6][7][8][9].Recently, the transient directing group strategy (TDGS) has been well applied in the field of transition metal-catalyzed C-H bond functionalization of aldehydes, ketones, and amines [10][11][12][13][14][15].In 2016, the Yu group reported the Pd-catalyzed C-H arylation of o-alkyl benzaldehydes and aliphatic ketones by employing α-amino acids as transient directing groups [16].Meanwhile, our group also disclosed the first example of Pd-catalyzed direct β-C(sp 3 )-H arylation of aliphatic aldehydes by using either 3-aminopropanoic acid or 3-amino-3-methylbutanoic acid as a transient directing group [17].Although much significant progress has been made in this research area, the β-C(sp 3 )-H bond functionalization of tertiary aldehydes is rare with only a few examples reported [18,19].In 2017, the Bull group disclosed Pd-catalyzed β-C(sp 3 )-H arylation of tertiary aldehydes with simple N-tosylethylenediamine as transient directing group (Scheme 1a) [18].Later, the same group reported the Pd-catalyzed intramolecular β-C(sp 3 )-H arylation of tertiary aldehydes in the presence of 2-methoxyethan-1-amine (Scheme 1b) [19].In 2019, the Chen and Zhou group demonstrated Pd-catalyzed selective C-H arylation of phenylacetaldehydes using L-valine as the transient directing group (Scheme 1c) [20].Recently, the Yang and Li group used a calix [4]arene-derived diamine as the transient directing group to achieve this process (Scheme 1d) [21].Unfortunately, these strategies only provided limited examples with isolated yields no more than 63%.Therefore, the development of highly efficient methodologies with a broader substrate scope is desirable.

Results and Discussion
On the basis of our previous studies, we commenced our investigation on the reaction of pivalaldehyde (1a) and methyl 4-iodobenzoate (2a) in the presence of catalytic Pd(OAc) 2 and stoichiometric amounts of AgTFA with L-phenylglycine (TDG1, 40 mol%) and 3nitro-5-(trifluoromethyl)pyridin-2-ol (L1, 30 mol%) at 100 • C under a nitrogen atmosphere (Scheme 2 and Table 1).After an extensive solvent screening, it was determined that a mixture of HFIP and HOAc in a ratio of 3:1 yielded the desired arylated product 3a-mono (42% NMR yield) as well as the diarylated product 3a-di (34% NMR yield) (Table 1, entries 1-6).The subsequent investigation on the amounts of L1 and TDG1 revealed that increasing the loading of L1 (from 40 to 60 mol%) resulted in an enhancement in the yields of 3a-mono and 3a-di to 53% and 35%, respectively (Table 1, entries 7-12).Furthermore, no significant improvements were observed when employing alternative Pd catalysts, such as Pd(TFA) 2 , PdCl 2 , and PdBr 2 (Table 1, entries 13-15).In the absence of the 2-pyridone ligand, both the yields of 3a-mono and 3a-di decreased, while no products were obtained in the absence of a transient directing group (

Results and Discussion
On the basis of our previous studies, we commenced our investigation on the reaction of pivalaldehyde (1a) and methyl 4-iodobenzoate (2a) in the presence of catalytic Pd(OAc)2 and stoichiometric amounts of AgTFA with L-phenylglycine (TDG1, 40 mol%) and 3-nitro-5-(trifluoromethyl)pyridin-2-ol (L1, 30 mol%) at 100 °C under a nitrogen atmosphere (Scheme 2 and Table 1).After an extensive solvent screening, it was determined that a mixture of HFIP and HOAc in a ratio of 3:1 yielded the desired arylated product 3a-mono (42% NMR yield) as well as the diarylated product 3a-di (34% NMR yield) (Table 1, entries 1-6).The subsequent investigation on the amounts of L1 and TDG1 revealed that increasing the loading of L1 (from 40 to 60 mol%) resulted in an enhancement in the yields of 3amono and 3a-di to 53% and 35%, respectively (Table 1, entries 7-12).Furthermore, no significant improvements were observed when employing alternative Pd catalysts, such as Pd(TFA)2, PdCl2, and PdBr2 (Table 1, entries 13-15).In the absence of the 2-pyridone ligand, both the yields of 3a-mono and 3a-di decreased, while no products were obtained in the absence of a transient directing group (     Next, the effect of both transient directing groups and 2-pyridone ligands on this reaction was examined (Scheme 3).While the use of α-amino acids TDG1-5 afforded the monoand di-arylated products in good yields, 2-aminoisobutyric acid (TDG6) proved inefficient.Furthermore, β-amino acids TDG7-10 failed to provide any desired products.These results suggest that L-phenylglycine (TDG1) was the optimal transient directing group, presumably via formation of a [5,5]-bicyclic palladium species in this protocol.The subsequent screening of 2-pyridone derivatives revealed that 3-nitro-5-(trifluoromethyl)pyridin-2-ol (L1) was the optimal ligand, while other 2-pyridone ligands L2-10 provided only moderate yields.Next, the effect of both transient directing groups and 2-pyridone ligands on this reaction was examined (Scheme 3).While the use of α-amino acids TDG1-5 afforded the mono-and di-arylated products in good yields, 2-aminoisobutyric acid (TDG6) proved inefficient.Furthermore, β-amino acids TDG7-10 failed to provide any desired products.These results suggest that L-phenylglycine (TDG1) was the optimal transient directing group, presumably via formation of a [5,5]-bicyclic palladium species in this protocol.The subsequent screening of 2-pyridone derivatives revealed that 3-nitro-5-(trifluoromethyl)pyridin-2-ol (L1) was the optimal ligand, while other 2-pyridone ligands L2-10 provided only moderate yields.With the optimized reaction conditions at hand, the substrate scope study of aryl iodides was carried out (Scheme 4).The presence of a strong electron-withdrawing (ester, cyano, nitro, and trifluoromethyl) group on the phenyl ring at the para-or meta-position of iodobenzene was found to be compatible with our current catalytic process, resulting in the isolation of desired mono-and di-arylated products 3a-g with good overall yields.With the optimized reaction conditions at hand, the substrate scope study of aryl iodides was carried out (Scheme 4).The presence of a strong electron-withdrawing (ester, cyano, nitro, and trifluoromethyl) group on the phenyl ring at the paraor meta-position of iodobenzene was found to be compatible with our current catalytic process, resulting in the isolation of desired mono-and di-arylated products 3a-g with good overall yields.Notably, the synthetic applicability of this protocol could be further enhanced by facile conversion of these well-tolerated functional groups into other important moieties.As expected, this catalytic system also exhibited compatibility with 5-iodo-2-(trifluoromethyl)pyridine, providing the desired mono-arylated product 3h in moderate yield.To our delight, natural products-containing aryl iodide derived from complex organic frameworks, including menthol and fenchol, could also be efficiently converted into the desired products 3i-j with high overall yields.However, the use of TDG1 and L1 yielded only moderate yields when employing unsubstituted or electron-donating substituted iodobenzenes as coupling partners, as well as weakly electron-withdrawing iodobenzenes.The utilization of TDG2 and L2 resulted in a significant enhancement in the overall yields of 3k (from 43% to 66%).Furthermore, the desired products 3l-o were obtained with good yields from iodobenzenes bearing a methoxy, methyl, or halogen group.
Molecules 2024, 29, x FOR PEER REVIEW 5 of 16 delight, natural products-containing aryl iodide derived from complex organic frameworks, including menthol and fenchol, could also be efficiently converted into the desired products 3i-j with high overall yields.However, the use of TDG1 and L1 yielded only moderate yields when employing unsubstituted or electron-donating substituted iodobenzenes as coupling partners, as well as weakly electron-withdrawing iodobenzenes.
The utilization of TDG2 and L2 resulted in a significant enhancement in the overall yields of 3k (from 43% to 66%).Furthermore, the desired products 3l-o were obtained with good yields from iodobenzenes bearing a methoxy, methyl, or halogen group.Subsequently, the substrate scope study of aliphatic aldehydes was carried out (Scheme 5).The α-methyl-α,α-dialkyl acetaldehydes, such as 2-methyl-2-propylpentanal, 2-methyl-2propylhexanal, and 2-methyl-2-propylheptanal, produced only the mono-arylated products 3p-3r in good yields.Furthermore, a tertiary aliphatic aldehyde bearing a cyclohexyl group also provided the desired product 3s in 55% yield.These results indicate that the functionalization of the methyl β-C-H bond is predominantly favored over the methylene β-C-H bond.Additionally, when α,α-dimethyl-α-aryl acetaldehydes were employed, only mono-arylated products 3t-u were obtained in moderate to good yields.It is noteworthy that the ether group was also tolerated and both mono-and di-arylated products 3v-w were isolated with good overall yields.Unfortunately, non-α-quaternary aliphatic aldehydes, including cyclohexanal, 2-methylpentaldehyde, and n-pentanal, failed in our current catalytic cycle (3x-z).
Molecules 2024, 29, x FOR PEER REVIEW 6 of 16 2-methyl-2-propylhexanal, and 2-methyl-2-propylheptanal, produced only the mono-arylated products 3p-3r in good yields.Furthermore, a tertiary aliphatic aldehyde bearing a cyclohexyl group also provided the desired product 3s in 55% yield.These results indicate that the functionalization of the methyl β-C-H bond is predominantly favored over the methylene β-C-H bond.Additionally, when α,α-dimethyl-α-aryl acetaldehydes were employed, only mono-arylated products 3t-u were obtained in moderate to good yields.It is noteworthy that the ether group was also tolerated and both mono-and di-arylated products 3vw were isolated with good overall yields.Unfortunately, non-α-quaternary aliphatic aldehydes, including cyclohexanal, 2-methylpentaldehyde, and n-pentanal, failed in our current catalytic cycle (3x-z).

General Information
All the solvents and commercially available reagents were purchased and used directly.Thin layer chromatography (TLC) was performed on EMD precoated plates (silica gel 60 F254, Art 5715, Yantai Jiangyou Silica gel Development Co., LTD, Yantai, China) and visualized by fluorescence quenching under UV light.Column chromatography was performed on EMD Silica Gel 60 (200-300 Mesh, Shanghai Titan Technology Co., Ltd., Shanghai, China) using a forced flow of 0.5-1.0bar.The 1 H and 13 C NMR spectra were obtained on a Bruker AVANCE III-300 or 400 spectrometer (Bruker Corporation, Billerica, Massachusetts, USA). 1 H NMR data was reported as: chemical shift (δ ppm), multiplicity, coupling constant (Hz), and integration. 13C NMR data was reported in terms of chemical shift (δ ppm), multiplicity, and coupling constant (Hz).Mass (HRMS) analysis was obtained using Agilent 6200 Accurate-Mass TOF LC/MS (Agilent Technologies Co., Ltd., Santa Clara, California, USA).system with Electrospray Ionization (ESI).Aliphatic aldehydes 1 Scheme 6. Plausible catalytic cycle.

Optimization of the Reaction Conditions
A 10 mL Schlenk tube was charged with methyl 4-iodobenzoate (2a, 104.81 mg, 0.4 mmol), L-phenylglycine (TDG1), 3-nitro-5-(trifluoromethyl)pyridin-2-ol (L1), Pd source (0.02 mmol), and AgTFA (0.3 mmol).The tube was evacuated and filled with N 2 three times.Next, pivalaldehyde (1a, 22.0 µL, 0.2 mmol) and the solvents were added into the tube quickly.The reaction was then stirred vigorously at room temperature for 20 min before being heated to 100 • C for 24 h.After cooling to room temperature, the reaction mixture was diluted with EtOAc (15 mL), filtered through a pad of celite, and the filtrate was then concentrated in vacuo; the crude product was analyzed by 1 H NMR in CDCl 3 .Yields are based on 1a, determined by crude 1 H NMR using dibromomethane as the internal standard.The residue was purified by flash chromatography on silica gel using petroleum ether/EtOAc (v/v = 10:1) as the eluent to yield products 3a-mono and 3a-di.

Synthetic Procedures for the Synthesis of Compound 3
A 10 mL Schlenk tube was charged with iodobenzene (2, 0.4 mmol), transient directing groups (TDG1 or TDG2, 0.08 mmol), 2-pyridone ligands (L1 or L2, 0.12 mmol), Pd(OAc) 2 (4.53 mg, 0.02 mmol), and AgTFA (66.27 mg, 0.3 mmol).The tube was evacuated and filled with N 2 three times.Next, aldehyde (1, 0.2 mmol) and the mixture of HFIP (1.5 mL) and HOAc (0.5 mL) were added into the tube quickly.The reaction was then stirred vigorously at room temperature for 20 min before being heated to 100 • C for 24 or 72 h.After cooling to room temperature, the reaction mixture was diluted with EtOAc (15 mL), filtered through a pad of celite, and the filtrate was then concentrated in vacuo; the residue was purified by flash chromatography on silica gel using petroleum ether/EtOAc as the eluent to yield the product 3.

Conclusions
In summary, we have developed a palladium-catalyzed direct methyl β-C(sp 3 )-H arylation reaction of tertiary aliphatic aldehydes with the commercially available α-amino acids as the transient directing groups and 2-pyridones as external ligands.Furthermore, a good functional group compatibility was observed in this catalytic cycle, and a variety of aryl iodides were efficiently coupled with different tertiary aliphatic aldehydes, providing the desired arylated aldehydes in moderate to good yields.A further application study is currently ongoing in our laboratory.

Table 1 .
Optimization of reaction conditions.
a Entry

Table 1 .
Optimization of reaction conditions.