Bifunctional N-heterocyclic carbene ligands for Cu-catalyzed direct C–H carboxylation with CO2

The use of N-heterocyclic carbenes (NHCs) as strong s-donating ligands has become increasingly popular in homogeneous catalysis. Numerous structural variations on the prototypical imidazolylidene skeleton have been used to modulate the electronic and steric properties of NHC ligands. Imidazo[1,5-a] pyridin-3-ylidene (ImPy) ligands, rst developed by Glorius and Lassaletta in 2005, are a rigid bicyclic variant of NHCs. ImPy ligands are strong s-donors as the extended p-system can increase the electron density at the carbene center. Substituents on the bicyclic ImPy can be projected into the metal coordination sphere, oen resulting in bonding interactions with the metal. Synthesis of ImPy precursors is concise and oen allows late-stage incorporation of diverse functional substituents. Owing to this feature, a number of ImPy-metal catalysts have been developed for various organic transformations (Fig. 1). We envision that ImPy ligands could serve as a versatile framework for bifunctional NHC ligands. Polyether units such as polyethylene glycol (PEG) are known as a CO2-philic building block and have been utilized in ionic liquids for CO2 capture and as catalysts for CO2 conversion. Thus we were wondering whether introduction of diethylene glycol unit (DEG) into the ligand scaffold could render the ImPy bifunctional. Herein, we report the synthesis of diethylene glycol-functionalized imidazo[1,5-a]pyridin-3-ylidene (DEGImPy) copper complexes and their application in direct C–H carboxylation of benzoxazoles with CO2. DEG-ImPy Cu exhibits


Introduction
The use of N-heterocyclic carbenes (NHCs) as strong s-donating ligands has become increasingly popular in homogeneous catalysis. 1 Numerous structural variations on the prototypical imidazolylidene skeleton have been used to modulate the electronic and steric properties of NHC ligands. Imidazo [1,5-a] pyridin-3-ylidene (ImPy) ligands, rst developed by Glorius 2 and Lassaletta 3 in 2005, are a rigid bicyclic variant of NHCs. ImPy ligands are strong s-donors 3,4 as the extended p-system can increase the electron density at the carbene center. 5 Substituents on the bicyclic ImPy can be projected into the metal coordination sphere, oen resulting in bonding interactions with the metal. 3,6 Synthesis of ImPy precursors is concise and oen allows late-stage incorporation of diverse functional substituents. 7 Owing to this feature, a number of ImPy-metal catalysts have been developed for various organic transformations ( Fig. 1). 8 We envision that ImPy ligands could serve as a versatile framework for bifunctional NHC ligands. 9 Polyether units such as polyethylene glycol (PEG) are known as a CO 2 -philic building block and have been utilized in ionic liquids for CO 2 capture 10 and as catalysts for CO 2 conversion. 11 Thus we were wondering whether introduction of diethylene glycol unit (DEG) into the ligand scaffold could render the ImPy bifunctional. Herein, we report the synthesis of diethylene glycol-functionalized imidazo [1,5-a]pyridin-3-ylidene (DEG-ImPy) copper complexes and their application in direct C-H carboxylation of benzoxazoles with CO 2 . DEG-ImPy Cu exhibits higher catalytic activity than non-functionalized NHC-Cu catalysts.

X-ray crystallography
The structure of ImPy-Cu complex 5a and 5g were determined by X-ray diffraction analysis (Fig. 2). As with recently reported ImPy-copper complexes, 8j geometry of both complexes is linear; C(1)-Cu(1)-Cl(1) 173.5(1) (5a) and 173.7(4) (5g). In case of 5g, the mesityl group is in close proximity to the Cu metal center as the observed atom distance Cu(1)-C(8) is shorter (2.887Å) than that of 5a (2.957Å). The aryl group on the nitrogen atom in 5a is oriented nearly perpendicular to the NHC plane, resulting in a dihedral angle of 80.64 whereas the dihedral angle between the ImPy plane and the DEG-phenyl in 5g is 50.84 .

Catalytic properties of ImPy-Cu complexes
With the various ImPy ligands in hand, the catalytic activities of the ImPy-Cu complexes were evaluated in direct C-H carboxylation of benzoxazole using CO 2 (Table 1). Synthetic utilization of carbon dioxide (CO 2 ) as a sustainable C1 feedstock has attracted much attention recently. 14 Catalytic direct C-H carboxylation with CO 2 is an atom-economical transformation that affords carboxylic acid derivatives. Various C-H bonds of alkynes, 15 alkenes/arenes, 16,17 and alkanes, 18 can be substituted with CO 2 H. Coinage-metal complexes with NHC ligands are efficient catalysts for direct C-H carboxylation. Following the procedure reported in the literature, 16c initial studies were carried out using isolated NHC-Cu complexes (entries 1-4). ImPy-Cu complex with a 2,6-diisopropyl phenyl substituent (5c) showed higher catalytic activity in producing the corresponding ester than IPrCuCl under the same conditions (entry 4 vs. entry 1). It was examined whether the catalyst could be generated in situ from CuCl and NHC$HCl salt under the same reaction conditions. In most cases, in situ-formed catalysts from CuCl and NHC ligands showed better yields than the isolated Cu complexes (entries 5-7 vs. entries 1-3). Note that in situ-generated Cu catalysts from alkoxy-functionalized ImPy ligands exhibited very good yields (entries 10-12). While the hydroxy group (4d) was rather detrimental (entry 9), a methoxy group (4e and 4f) resulted in increased yield (entries 10 and 11). ImPy ligand bearing a diethylene glycol moiety (4g, DEG-ImPy) exhibited excellent activity and afforded the desired product in quantitative yield (entry 12).
Using the optimal DEG-ImPy ligand (4g), the heteroarene substrate scope of the direct C-H carboxylation was examined Scheme 1 Synthesis of DEG-ImPy ligands and ImPy-Cu(I) complexes.  under the same conditions (Scheme 2). Overall, reactions with a variety of substituted benzoxazoles proceeded smoothly. Methyl-substituted benzoxazoles (7b-7d), regardless of the position of methyl group on the heterocyclic ring, gave high yields (92-98%). From the reactions with benzoxazoles containing electron donating (R ¼ OMe, Ph) and withdrawing group such as halide (R ¼ Cl, Br), the corresponding esters were obtained with yields of over 90%. The reaction also works for other heteroarene compounds, as the reaction with 2-phenyl-1,3,4-oxadizole afforded product 7j with an 83% yield. However, N-methylbenzoimidazole afforded the product 7k with a 6% yield. As shown in Scheme 3, the Cu catalyst with DEG-ImPy$HCl (4g) exhibits superior catalytic activity than that with IPr$HCl as well as plain ImPy$HCl (4a). Use of ImPy ligand and introduction of a potential cation-binding DEG unit in the ligand framework resulted in improving the catalytic activity in the direct C-H carboxylation with CO 2 .

Conclusions
Diethylene glycol-functionalized imidazo[1,5,a] pyridin-3ylidenes (DEG-ImPy) ligands have been developed as a bifunctional NHC ligand. Cu catalyst generated in situ with the DEG-ImPy$HCl salts efficiently catalyzed the direct C-H carboxylation of various heterocyclic compounds with CO 2 , resulting in higher yields than those with the imidazolylidene carbene ligand (IPr). Further studies of DEG-ImPy ligands relating to cation-binding capabilities as well as application in other catalysis are currently under way in our laboratory.

General remarks
All reactions were carried out under an inert argon atmosphere using the Schlenk technique or a glovebox. All reactions using CO 2 were conducted in a 30 mL Schlenk ask equipped with Teon-valve. Nuclear magnetic resonance (NMR) spectra were recorded on a JEOL spectrometer, operating at 400 MHz or 300 MHz for 1 H NMR and at 100 MHz or 75 MHz for 13 C NMR. All chemical shis for 1 H and 13 C NMR spectroscopy were assigned to residual signals from CDCl 3 ( 1 H) at 7.26 ppm and ( 13 C) at 77.16 ppm, CD 2 Cl 2 ( 1 H) at 5.32 ppm and ( 13 C) at 53.84 ppm, or DMSO-d 6 ( 1 H) at 2.50 ppm and ( 13 C) at 39.52 ppm. High resolution GC mass spectra were recorded using a JEOL JMS-700 MStation mass spectrometer. Infrared spectra were obtained on a Nicolet iS10 FT-IR spectrometer with an ATR unit and recorded in wave numbers (cm À1 ).

Materials
Tetrahydrofuran (THF), dichloromethane (CH 2 Cl 2 ), N,N-dimethylformamide (DMF) and diethyl ether (Et 2 O) were dried under a positive pressure of dry nitrogen using a J. C. Meyer Solvent Purication System prior to use. Toluene and n-hexane were distilled from calcium hydride and ethanol was dried over 4Å molecular sieves. Unless specied, all the other chemicals were purchased from Sigma-Aldrich Co., Acros Organics, TCI, Alfa Aesar, and Strem Chemicals Inc. and were used as received without further purication. Commercial carbon dioxide (99.99%) was purchased by Sinil Gas Co. and used without further purication. Benzoxazole, 5-methylbenzoxazole, and 5-chlorobenzoxazole were purchased and puried by ash column chromatography. Other benzoxazole derivatives 19 and oxadiazole 20 were synthesized as reported previously. 6-Bromopicolinaldehyde (2), 12 6-mesitylpicolinaldehyde (3), 13  EtOH (1.20 mL) and stirred at room temperature for 12 hours. The crude product was puried by ash column chromatography (CH 2 Cl 2 : MeOH 10 : 1). The product was collected by reprecipitation using Et 2 O and CH 2 Cl 2 to obtain a product 4a (216 mg, 92%) as an ivory powder. 1  2-(2-Hydroxyphenyl)-5-mesityl-2H-imidazo[1,5-a]pyridinium chloride (4d). Compound 4d was prepared analogously to 4a. 4d was synthesized from 2-aminophenol and 6-mesitylpicolinaldehyde 3. The crude product was puried by recrystallization using Et 2 O and CH 2 Cl 2 to obtain a product 4d (quant.) as an ivory powder. 1    (2,5-Dimesityl imidazo[1,5-a]pyridinyl)copper(I) chloride (5a). 2,5-Dimesityl imidazo[1,5-a]pyridinium chloride 4a (39.1 mg, 0.100 mmol), copper chloride(I) (9.90 mg, 0.100 mmol), and sodium tert-butoxide (10.6 mg, 0.110 mmol) were dissolved in THF (2.50 mL). The reaction mixture was stirred at room temperature overnight. The crude product was puried by ash column chromatography (n-hexane : ethyl acetate 3 : 1) and concentrated under reduced pressure to obtain a product 5a as a green powder with 76% yield. Single crystals suitable for crystallography were obtained by liquid diffusion of n-hexane into a saturated ethyl acetate solution at room temperature. 1  (2-Adamantyl-5-mesityl imidazo[1,5-a]pyridinyl) copper(I) chloride (5b). With the same method used in the synthesis of 5a, compound 5b was obtained as a white powder with 64% yield from 4b. 1 138.8, 136.3, 130.1, 129.9, 129.7, 122.5, 116.6, 114.8, 108.2, 59.6 (2-(2,6-Diisopropylphenyl)-5-mesityl imidazo[1,5-a]pyridinyl)copper(I) chloride (5c). With the same method used in the synthesis of 5a, compound 5c was obtained as a pale yellow powder with 96% yield from 4c. 1  a]pyridinium chloride 4g (149 mg, 0.320 mmol) and silver(II)oxide (74 mg, 0.320 mmol) were dissolved in CH 2 Cl 2 (7.40 mL). The reaction mixture was stirred at room temperature overnight in the dark. The mixture was then ltered through a Celite pad and washed with CH 2 Cl 2 . The crude product was dissolved in CH 2 Cl 2 (14 mL) and copper chloride(I) (63 mg, 0.640 mmol) was added in one portion. The reaction was stirred at room temperature overnight. The mixture was then ltered through a Celite pad and washed with CH 2 Cl 2 . The crude product was puried by ash column chromatography (n-hexane : ethyl acetate 1 : 6) and concentrated under reduced pressure to obtain a product 5g as an ivory powder with 79% yield. Single crystals suitable for crystallography were obtained by liquid diffusion of n-hexane into a saturated benzene or THF solution at room temperature. 1  2-(2-Methoxyethoxy)ethyl 4-methylbenzenesulfonate (8). Diethylene glycol monomethyl ether (6.01 g, 50 mmol), p-toluene sulfonyl chloride (11.4 g, 60 mmol), and pyridine (8.09 mL, 100 mmol) were combined at 0 C, then stirred for 6 h at the same temperature. The reaction mixture was extracted with Et 2 O and water, and washed with 1 N HCl. The organic phase was dried over anhydrous MgSO 4 , ltered, and concentrated in a vacuum. The crude product was puried by ash column chromatography (n-hexane : ethyl acetate 3 : 1) to give a product 8 (90%) as a colorless oil. 1  2-(2-(2-Methoxyethoxy)ethoxy)aniline (9). To a solution of 2-nitrophenol (139 mg, 1.00 mmol) and potassium carbonate (138 mg, 1.00 mmol) in DMF (3.50 mL) was added a solution of 2-(2-methoxyethoxy)ethyl 4-methylbenzenesulfonate 8 (274 mg, 1.00 mmol) in DMF (2.00 mL) and allowed to reux overnight. Aerward, the mixture was cooled to room temperature. The solvent was evaporated and the residue was dissolved in ethyl acetate. The organic phase was washed with water, dried over anhydrous MgSO 4 , then ltered and concentrated in a vacuum. The crude mixture was subjected to hydrogenation over Pd/C in MeOH (8.00 mL) at room temperature under H 2 atmosphere for 24 h. Pd/C was ltered through a Celite pad and the ltrate was concentrated under reduced pressure. The crude product was puried by ash column chromatography (n-hexane : ethyl acetate 2 : 1) to give a product 9 (84%, 2 steps) as a dark orange oil. 1  General procedures for ImPy Cu-catalyst generated in situ for direct C-H carboxylation of heterocyclic compound. General procedures were adapted from those used by Hou et al. 16c Ligand (5 mol%), copper chloride(I) (2.50 mg, 5 mol%), and potassium tert-butoxide (65.1 mg, 0.580 mmol) were added to a 30 mL Schlenk ask equipped with Teon-valve in a glove box. THF (2.50 mL) was added to the reaction ask and stirred at room temperature for 4 hours. Under an Ar atmosphere, a heterocyclic compound (59.6 mg, 0.500 mmol) was added to the reaction mixture. The mixture was degassed through three freeze-pump-thaw cycles and CO 2 (1 atm) was charged into the reaction ask. The sealed Schlenk ask was stirred at 80 C for 14 hours. Aer the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. DMF (2.50 mL) and 1-iodohexane (0.150 mL, 1.00 mmol) were added to the mixture under an Ar atmosphere and stirred at 80 C for 6 hours. The reaction mixture was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous Na 2 SO 4 , ltered, and concentrated in a vacuum. The crude product was puried by ash column chromatography (nhexane : ethyl acetate 8 : 1) to give the product.
General procedures for ImPy Cu-catalyzed carboxylation of benzoxazole with CO 2 . ImPy-Cu complexes (5 mol%) and potassium tert-butoxide (61.7 mg, 0.550 mmol) were added to a 30 mL Schlenk ask equipped with Teon-valve in a glove box and THF (2.50 mL) was charged into the reaction ask. Benzoxazole (59.6 mg, 0.500 mmol) was added and the mixture was degassed through three freeze-pump-thaw cycles. CO 2 (1 atm) was charged into the reaction ask. The reaction mixture was stirred at 80 C for 14 hours. Aer the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. DMF (2.50 mL) and 1-iodohexane (0.150 mL, 1.00 mmol) were added to the mixture under an Ar atmosphere and stirred at 80 C for 6 hours. Subsequent procedures remained the same as described above.

Conflicts of interest
There are no conicts to declare.