Nickel-catalyzed Suzuki–Miyaura cross-couplings of aldehydes

Transition-metal-catalyzed cross-couplings have been extensively used in the pharmaceutical and agrochemical industries for the construction of diverse C–C bonds. Conventional cross-coupling reactions require reactive electrophilic coupling partners, such as organohalides or sulfonates, which are not environmentally friendly and not naturally abundant. Another disadvantage associated with these transformations is the need for an exogenous base to facilitate the key transmetalation step, and this reagent inevitably induces side reactions and limits the substrate scope. Here, we report an unconventional Suzuki-type approach to the synthesis of biaryls, through nickel-catalyzed deformylative cross coupling of aldehydes with organoboron reagents under base-free conditions. The transformation tolerates structurally diverse (hetero)aryl substituents on both coupling partners and shows high reactivity and excellent functional group tolerance. Furthermore, the protocol was carried out on gram scale and successfully applied to the functionalization of complex biologically active molecules. Mechanistic investigations support a catalytic cycle involving the oxidative addition of the nickel into the aldehyde C(acyl)–H bond with subsequent hydride transfer, transmetalation, decarbonylation and reductive elimination processes.


Supplementary Note 1. General Information
Unless otherwise noted, all commercially available compounds were used as provided without further purification. Solvents for chromatography were technical grade and freshly distilled prior to use.
Analytical thin-layer chromatography (TLC) was performed on Merck silica gel aluminium plates with F-254 indicator, visualised by irradiation with UV light. Column chromatography was performed using silica gel (Macherey Nagel, particle size 0.040-0.063 mm). Solvent mixtures are understood as volume/volume. 1 H-NMR, 13 C-NMR and 19 F-NMR were recorded on a Varian AV400 or AV600 spectrometer in CDCl 3  IR spectra were recorded on a Perkin Elmer-100 spectrometer and are reported in terms of frequency of absorption (cm -1 ). Mass spectra (EI-MS, 70 eV) were conducted on a Finnigan SSQ 7000 spectrometer.
HRMS were recorded on a Thermo Scientific LTQ Orbitrap XL spectrometer.

Supplementary Note 2. Procedure for the screening of air-stable Ni precatalyst
Procedure: A 10-mL oven-dried sealed tube containing a stirring bar was charged with Ni(II) precatalyst (x mol%) and reductant (z equiv.) under the protection of argon. Subsequently, HPLC grade 1,4-dioxane (1.5 mL) was added by syringe and trioctylphosphine ligand (y mol%) was injected by microsyringe.

Supplementary
An oven-dried Schlenk flask was charged under nitrogen with 4-bromofuran-2-carbaldehyde S1 (542 mg, 3.1 mmol), (4-(tert-butyl)phenyl)boronic acid S2 (662 mg, 3.7 mmol), Pd(PPh 3 ) 4 (54 mg, 1.5 mol%), Na 2 CO 3 (aq, 3 mL, 2 M) and 1,4-dioxane (15 mL). The Schlenk tube was sealed under nitrogen and placed in an oil bath preheated to 80 °C and the reaction mixture was stirred overnight at this temperature. After being cooled to room temperature, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 , and then filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography to afford 1w as a white solid (518 mg, 73%).  Substrates 2bb and 2cc in Supplementary Figure 2 were prepared according to general method C.

General Method C:
Compound S9 was synthesized from estrone according to the reported method. 5 An

Supplementary Note 5.
General procedure for the deformylative coupling and spectroscopic data of the products In a nitrogen-filled glovebox, a 10-mL oven-dried sealed tube containing a stirring bar was charged with the corresponding aldehyde 1 (0.20 mmol, 1.0 equiv.), aryl/heteroaryl boronic ester 2 (0.40 mmol, 2.0 equiv.) and yellow Ni(cod) 2 (5.5 mg, 10 mol%). Subsequently, HPLC grade 1,4-dioxane (1.5 mL) was added, and then trioctylphosphine ligand (18 μL, 20 mol%) and 2,2,2-trifluoroacetophenone (42 μL, 0.30 mmol, 1.5 equiv.) were added respectively via microsyringe. The tube with the mixture was sealed and removed from the glovebox. After stirring at 160 °C for 36 h, the mixture was allowed to cool to room temperature, diluted with EtOAc (5 mL) and filtered through a celite plug, eluting with additional EtOAc (15 mL). The filtrate was concentrated and purified by column chromatography on silica gel to yield the title product.

3-Phenylpyridine (3Aa)
Following the general procedure, the title product was isolated as colorless oil after flash chromatography on silica gel. 1

3-(p-Tolyl)pyridine (3Ab)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

3-(4-(Tert-butyl)phenyl)pyridine (3Ac)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

3-(Naphthalen-2-yl)pyridine (3Af)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

3-(Naphthalen-1-yl)pyridine (3Ag)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

3-(4-Ethoxyphenyl)pyridine (3Aj)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

N,N-dimethyl-4-(pyridin-3-yl)aniline (3Al)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

3-(4-Fluorophenyl)pyridine (3Am)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

3-(2-Fluorophenyl)pyridine (3An)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

3-(3,5-Difluorophenyl)pyridine (3Ao)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel.

3-(3-(Trifluoromethyl)phenyl)pyridine (3Ap)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

3-(Pyridin-3-yl)benzonitrile (3As)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

Methyl 4-(pyridin-3-yl)benzoate (3At)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

3-(Benzofuran-2-yl)pyridine (3Av)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

3-(Benzo[b]thiophen-2-yl)pyridine (3Aw)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

3-(Furan-2-yl)pyridine (3Ax)
Following the general procedure, the title product was isolated as colorless oil after

3-(Furan-3-yl)pyridine (3Ay)
Following the general procedure, the title product was isolated as colorless oil after flash chromatography on silica gel. 1

3-(Thiophen-2-yl)pyridine (3Az)
Following the general procedure, the title product was isolated as colorless oil after flash chromatography on silica gel. 1

3-(Thiophen-3-yl)pyridine (3Aaa)
Following the general procedure, the title product was isolated as colorless oil after flash chromatography on silica gel. 1

1,1'-Biphenyl (3Ba)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

2-Phenylnaphthalene (3Ca)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

9-Phenylphenanthrene (3Da)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

2-Phenyl-9H-fluorene (3Fa)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

3-Methoxy-1,1'-biphenyl (3Ia)
Following the general procedure, the title product was isolated as colorless oil after flash chromatography on silica gel. 1

2-Methoxy-1,1'-biphenyl (3Ja)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

4-Phenylpyridine (3Sa)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1  (75), 138.9 (19); Data in accordance with the literature. 28

3-Phenylbenzo[b]thiophene (3Ua)
Following the general procedure, the title product was isolated as white solid after flash chromatography on silica gel. 1

4-Phenylquinoline (3Va)
Following the general procedure, the title product was isolated as colorless oil after flash chromatography on silica gel. 1
The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel to yield the title product 3Ba (80% yield, eluent: hexane) and 5 (67% yield, eluent: hexane/ethyl acetate = 10:1). Compound 3Ba: [   Supplementary Note 9. Computational methods All the geometries were optimized with the generalized gradient approximation (GGA) method with Gaussian 09, Revision D.01, 32 using meta-hybrid-GGA DFT functional ωB97xD. 33 The electronic configuration of all the non-metal elements was described with the Ahlrichs split-valance polarization basis function Def2-SVP while Ni is treated with the triple-ζ valence basis set Def2-TZVP. 34 dioxane, ε = 2.2099) were evaluated implicitly by a self-consistent reaction field (SCRF) approach for all the intermediates and transitions states, using the SMD continuum solvation model. 37 Unless specified otherwise, the ΔG was used throughout the text. The ΔG value was obtained by augmenting the E el energy terms at M06(SMD)/Def2-TZVPP with the respective free energy corrections at the ωB97xD/Def2-TZVP (Ni)/Def2-SVP (non-metal) level in gas phase. In all cases, the default integral grid (Fine Grid) was employed. The simplified trialkyl-phosphine ligand P n Pr 3 was used in the DFT calculation, which gave 53% yield (see Supplementary Table 1, entry 4). Ball and stick models are made using CYLView visualization programs. 38 Oxidative addition pathways. Based on our previous research, 39

Competition reactions between transmetalation and decarbonylation
Supplementary Figure 8. Competition reactions between transmetalation and decarbonylation. Blue path is transmetalation in the presence of one phosphine, while in alternative red path two phosphines are involved which is highly unfavorable by 19.1 kcal/mol. Orange pathway describes the decarbonylation prior to the transmetalation, which is also less favorable compared to the blue line.