Decarbonylative organoboron cross-coupling of esters by nickel catalysis

The Suzuki–Miyaura cross-coupling is a metal-catalysed reaction in which boron-based nucleophiles and halide-based electrophiles are reacted to form a single molecule. This is one of the most reliable tools in synthetic chemistry, and is extensively used in the synthesis of pharmaceuticals, agrochemicals and organic materials. Herein, we report a significant advance in the choice of electrophilic coupling partner in this reaction. With a user-friendly and inexpensive nickel catalyst, a range of phenyl esters of aromatic, heteroaromatic and aliphatic carboxylic acids react with boronic acids in a decarbonylative manner. Overall, phenyl ester moieties function as leaving groups. Theoretical calculations uncovered key mechanistic features of this unusual decarbonylative coupling. Since extraordinary numbers of ester-containing molecules are available both commercially and synthetically, this new ‘ester' cross-coupling should find significant use in synthetic chemistry as an alternative to the standard halide-based Suzuki–Miyaura coupling.

a. GC yield using dodecane as an internal standard. b. The reaction was conducted for 24 h using Ni(OAc) 2 (5 mol%) and P(n-Bu) 3  The number in the parenthesis shows the isolated yield.  Table 8. Calculated total (in a.u., at the M06L/BS1 level of theory) and relative energies (in kcal/mol) of the reactants, transition states, intermediates and products of the studied C(acyl)-O and C(aryl)-O oxidative addition of phenyl 3pyridinecarboxylate to Ni 3  Supplementary Table 9. Decarbonylative transmetalation in the absence of Na 2 CO 3 base. Calculated total (in a.u., at the M06L/BS1 level of theory) and relative energies (in kcal/mol) of the reactants, transition states, intermediates and products of the studied phenyl 3-pyridinecarboxylate and p-anisylboronic acid [i.e. MeOPh-B(OH) 2 ] cross-coupling catalyzed by Ni[P(n-Bu) 3 3 ] 2 (PyrCO)(OPh) and rearrangement. Calculated total (in a.u., at the M06L/BS1 level of theory) and relative energies (in kcal/mol) of the reactants, transition states, intermediates and products of the studied Na 2 CO 3 coordination to the phenyl 3-pyridinecarboxylate oxidative addition product Ni[P(n-Bu) 3 ] 2 (PyrCO)(OPh) and following multi-step rearrangement of the resulted intermediates. For cartesian coordinates of all reported structure see Supplementary

Preparation of Arenecarboxylic Acid Phenyl Esters 1 2-1. Method A
Thionyl chloride (0.5 M) was added to the carboxylic acid (1.0 equiv) and the mixture was refluxed for 1 h. The solution was concentrated in vacuo. To the residue were added CH 2 Cl 2 (0.5 M), phenol (1.0 equiv), and then N,N-dimethyl-4-aminopyridine (DMAP: 1 mol%). After cooling the mixture to 0 °C, triethylamine (Et 3 N: 1.2 equiv) was slowly added and then the reaction mixture was warmed to room temperature. After stirring the mixture for 1 h, NaHCO 3 aq was added to the resulting mixture to quench the reaction. The mixture was extracted three times with CH 2 Cl 2 . The combined organic layer was dried over Na 2 SO 4 , and then filtrated. The filtrate was concentrated in vacuo and the residue was purified by recrystallization or flash column chromatography to afford the corresponding phenyl ester 1.

1Y
To a round-bottomed flask with the carboxylic acid (1.0 equiv) were added phenol (1.0 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl: 1.1 equiv), N,N-dimethyl-4-aminopyridine (DMAP: 0.25 equiv) and CH 2 Cl 2 (0.5 M). After stirring the mixture for several hours with monitoring reaction progress with TLC, the reaction was quenched with saturated NaHCO 3 aq and extracted three times with CH 2 Cl 2 . The combined organic layer was dried over Na 2 SO 4 , filtrated, and concentrated in vacuo. The residue was purified by recrystallization or flash column chromatography to afford the corresponding phenyl ester 1.

One-pot Transformation of Thiophene-2-carboxylic Acid to Biaryl 3Ka
A 20-mL glass vessel equipped with J. Young ® O-ring tap containing a magnetic stirring bar was dried with heatgun under reduced pressure and filled with N 2 gas after cooling to room temperature. To this was added thiophene-2-carboxylic acid (51.3 mg, 0.40 mmol), diphenyliodonium triflate (172.0 mg, 0.40 mmol, 1.0 equiv), K 2 CO 3 (55.2 mg, 0.40 mmol, 1.0 equiv), and then toluene (2.0 mL). The vessel was sealed with O-ring tap and then heated at 130 °C for 2 h in an 8-well reaction block with stirring. After cooling the reaction mixture to room temperature, this mixture was concentrated in vacuo to remove toluene and iodobenzene.
To the same tube containing obtained crude product 1K were added Ni(OAc) 2 (3.5 mg, 0.02 mmol, 5 mol%), p-methoxyphenylboronic acid 3 (0.60 mmol, 91.9 mg, 1.5 equiv), and Na 2 CO 3 (84.8 mg, 0.8 mmol, 2.0 equiv). The vessel was vacuumed and refilled N 2 gas three times. To this was added P(n-Bu) 3 (19.0 mL, 0.08 mmol, 20 mol%) and toluene (1.6 mL). The vessel was sealed with O-ring tap and then heated at 150 °C for 24 h in an 8-well reaction block with stirring. After cooling the reaction mixture to room temperature, the mixture was passed through a short silica gel pad with EtOAc. The filtrate was concentrated and the residue was purified by flash column chromatography (hexane/EtOAc = 100:1) to afford 2-(4-methoxyphenyl)thiophene (3Ka: 46.2 mg, 61% yield over 2 steps) as a white solid.

Application to the Synthesis of Telmisartan Derivtives
To a test tube equipped with screw cap containing a magnetic stirring bar were added telmisartan (772 mg, 1.5 mmol, 1.0 equiv), phenol (155 mg, 1.65 mmol, 1.1 equiv), 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl: 316 mg, 1.65 mmol, 1.1 equiv), N,N-dimethyl-4-aminopyridine (DMAP: 18.3 mg, 0.15 mmol, 0.1 equiv) and CH 2 Cl 2 (3.0 mL). After stirring for 6 h, the reaction mixture was quenched with saturated NaHCO 3 aq and extracted three times with CH 2 Cl 2 . The combined organic layer was dried over Na 2 SO 4 , filtrated, and concentrated in vacuo. The residue was purified by flash column chromatography (hexane/EtOAc = 2:1 to EtOAc) to afford telmisartan Ph-ester (4: 850 mg, 96% yield) as a white solid. 1  O acid (2a: 91.8 mg, 0.60 mmol, 1.5 equiv), and Na 2 CO 3 (85.0 mg, 0.8 mmol, 2.0 equiv). The vessel was vacuumed and refilled N 2 gas three times. To this were added P(n-Bu) 3 (20 mL, 0.08 mmol, 20 mol%) and toluene (1.6 mL). The vessel was sealed with O-ring tap and then heated at 150 °C for 24 h in an 8-well reaction block with stirring. After cooling the reaction mixture to room temperature, the mixture was passed through a short silica gel pad with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (hexane/EtOAc = 100:1), and then GPC to afford 4'-methoxy- [ A 20-mL glass vessel equipped with J. Young ® O-ring tap containing a magnetic stirring bar and Cs 2 CO 3 (146.6 mg, 0.45 mmol, 1.5 equiv) was dried with a heatgun under reduced pressure and filled with N 2 gas after cooling to room temperature. To this vessel was added 4'-methoxy-[1,1'-biphenyl]-3-yl pivalate (7: 85.3 mg, 0.30 mmol, 1.0 equiv) and 2,3bis(dicyclohexylphosphine)thiophene (dcypt: 28.3 mg, 0.06 mmol, 20 mol%), and then introduced into an argon-atmosphere glovebox. To the reaction vessel was added Ni(cod) 2 (8.3 mg, 0.03 mmol, 10 mol%), and then taken out of the glovebox. To this tube were added benzoxazole (47.6 mg, 0.40 mmol, 1.3 equiv) and 1,4-dioxane (1.5 mL) under a stream of N 2 . The vessel was sealed with O-ring tap and then heated at 130 °C for 12 h in an 8-well reaction block with stirring. After cooling the reaction mixture to room temperature, the mixture was passed through a short silica gel pad with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (hexane/EtOAc = 100:1) to afford 2-(4'methoxy- [ A 20-mL glass vessel equipped with J. Young ® O-ring tap containing a magnetic stirring bar and Ni(OAc) 2 ·4H 2 O (5.0 mg, 0.020 mmol, 5 mol%) was dried with a heatgun for 1 min under reduced pressure and filled with N 2 gas after cooling to room temperature. To this vessel was added phenyl oxazole-4-carboxylate (1Q: 75.7 mg, 0.40 mmol, 1.0 equiv), pmethoxyphenylboroxine (2a': 80.3 mg, 0.20 mmol, 0.50 equiv), and Na 2 CO 3 (85.0 mg, 0.8 mmol, 2.0 equiv). The vessel was vacuumed and refilled with N 2 gas three times. To this were added P(n-Bu) 3 (20 mL, 0.08 mmol, 20 mol%) and toluene (1.6 mL). The vessel was sealed with O-ring tap and then heated at 150 °C for 24 h in an 8-well reaction block with stirring. After cooling the reaction mixture to room temperature, the mixture was passed through a short silica gel pad with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography by using Isolera ® (hexane/EtOAc = 95:5 to 4:1), and then GPC to afford 4-(4methoxyphenyl)oxazole (3Qa: 40.7 mg, 57% yield) as a white solid.

6-3. Orthogonal Coupling of 10
The solution of S6 (1.95 g, 7.0 mmol, 1.0 equiv) in THF (28 mL) was treated with 1M NaOHaq (14 mL, 2.0 equiv) at 50 °C. After stirring overnight, the mixture was diluted with Et 2 O and washed two times with Et 2 O. 1 M HClaq was added to the combined water phase to adjust the pH to 2, and then resulted solution was extracted three times with Et 2 O. The combined organic phase was concentrated in vacuo to afford 7-bromo-2-naphthoic acid (S7: 1.76 g) as a white solid. This was used without further purification.

Computational Details
Calculations were performed by Gaussian 09 quantum chemical package. 39 The geometries of all reported structures were optimized without symmetry constraints in toluene at the M06L level of density functional theory 40 in conjunction with the Lanl2dz basis set and corresponding Hay-Wadt ECP for Ni 41,42 . Standard 6-31G(d) basis sets were used for all other atoms. Below, this approach will be called as M06L/{Lanl2dz + [6-31G(d)]} or M06L/BS1. Solvent effects were estimated by using the PCM solvation method [43][44][45] . Previously, we have shown that this approach reasonable describes geometries and energetics of the Ni-complexes and Ni-catalyzed coupling reactions 46 . In order to incorporate disperse interactions into calculations we also performed geometry optimization and energy calculations of selected important intermediates and transition states at the M06/BS1 level of theory 47 .
The nature of each stationary point was characterized by performing normal mode analysis at the appropriate (i.e. same as a geometry optimization) levels of theory. Relative free