Iterative protecting group-free cross-coupling leading to chiral multiply arylated structures

The Suzuki–Miyaura cross-coupling is one of the most often utilized reactions in the synthesis of pharmaceutical compounds and conjugated materials. In its most common form, the reaction joins two sp2-functionalized carbon atoms to make a biaryl or diene/polyene unit. These substructures are widely found in natural products and small molecules and thus the Suzuki–Miyaura cross-coupling has been proposed as the key reaction for the automated assembly of such molecules, using protecting group chemistry to affect iterative coupling. We present herein, a significant advance in this approach, in which multiply functionalized cross-coupling partners can be employed in iterative coupling without the use of protecting groups. To accomplish this, the orthogonal reactivity of different boron substituents towards the boron-to-palladium transmetalation reaction is exploited. The approach is illustrated in the preparation of chiral enantioenriched compounds, which are known to be privileged structures in active pharmaceutical compounds.


General Experimental Conditions
Unless otherwise specified, all manipulations were carried out under at atmosphere of dry argon in oven-dried glassware or under a nitrogen atmosphere in an M. Braun glovebox with oxygen and water levels <2 ppm. Toluene, THF, and 1,2-dimethoxyethane (DME) were distilled from either calcium hydride (CaH 2 ) or sodium metal (Na), deoxygenated with a minimum of three freeze-pump-thaw cycles and stored under N 2 or Ar over molecular sieves (4Å) prior to use. operating at the denoted spectrometer frequency given in mega Hertz (MHz) for the specified nucleus. All NMR samples were prepared using CDCl 3 . To specify the signal multiplicity, the following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet; br indicates a broad resonance; app = apparent. Shifts are reported in parts per million (ppm) relative to tetramethylsilane (TMS) as an external standard for 1 H-and 13 C NMR spectra and calibrated against the solvent residual peak or in case of proteo-solvents against known solvent resonances. 2 SFC (supercritical fluid chromatography) traces for the assessment of enantiopurity were obtained from a JASCO Instruments SFC HPLC equipped with HPLC columns (CHIRALPAK IA, IB, IC, ID, IE, IF: length 250 mm, ø 4.6 mm, particle size 5 μm), operating at the stated flow-rate and pressure of supercritical CO 2 with the indicated amount of admixed modifier solvent or on a Berger SFC HPLC using the specified chiracel Berger Silica column and specified conditions of co-eluent, flow rate and pressure. Retention times are t R are given in minutes (min). Optical rotations [α] 22 D were measured on a Perkin-Elmer 241MC polarimeter as solutions in dichloromethane at concentration of 0.01 g mL -1 at 22 °C at 589 nm in a 0.5 dm cell, and given as specific rotations (° cm 2 g -1 ).
Data were consistent with those reported in the literature. 4 A racemic sample was prepared according to the procedure by Fernández and co-workers. 4 In order to determine the e.r. by SFC analysis the diboronate was oxidised to the diol by the following general procedure (GP1): To a solution of diboronate (1 mmol) in THF (5 mL) was added a 1:1 mixture of 2 M aq. NaOH/30% aq. H 2 O 2 (1 mL) at 0 °C. The mixture was warmed to RT and stirred until the reaction was complete by TLC analysis (usually less than 1 h). Water (5 mL) and Et 2 O (5 mL) were added and the layers were separated. The aqueous phase was extracted with Et 2 O (2 × 5 mL). The combined organics were washed with brine (10 mL), dried (MgSO 4 ), filtered and concentrated in vacuo.
The reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was cooled and concentrated in vacuo. Purification by column chromatography (hexane/EtOAc (93:7)) gave 5b as a white solid (440 mg, 79% yield).

Shown in Figure 4a
General Procedure 2: An oven dried pressure tube with a magnetic stir bar in a glovebox was charged with diboronate 8 (615.5 mg, 1.72 mmol, 1 equiv.), Pd 2 (dba) 3

Sequential Arylation of 11a
A 50 mL sealable glass vessel containing a magnetic stirring bar was flame-dried under vacuum and filled with argon after cooling to room temperature. To the glass vessel were added 11 (48.4 mg, 0.1 mmol), Pd 2 (dba) 3 (4.6 mg, 5 mol), P(t-Bu) 3 ·HBF 4 (26.1 mg, 20 mol), and K 2 CO 3 (41.5 mg, 0.3 mmol) under a stream of argon. Bromobenzene (12.5 L, 0.12 mmol), dry toluene (200 L) and H 2 O (10 L) were added, and then the vessel was sealed. The mixture was stirred at 80 °C for 24 h. After cooling to room temperature, reaction vessel was connected to a high vacuum line to remove excess bromobenzene and solvent for 6h. In independent experiments run not in series, complete conversion of substrate and formation of 1 st arylation product were checked by 1 H NMR using anisole as internal standard, resulting in 92% yield of the desired product.
After the vessel was filled with argon, Pd(OAc) 2 (2.2 mg, 10 mol), and RuPhos ( h. After cooling to room temperature, the mixture was passed through a pad of silica gel with copious washings with EtOAc (~15 mL). The filtrate was concentrated under reduced pressure.

Procedures for the Orthogonal Coupling in the Synthesis of Phosphodiesterase Inhibitor CDP 840 Shown in
The title compound was synthesized according to a modified literature procedure. 12 To a suspension of methyltriphenylphosphonium bromide (9.61 g, 26.9 mmol, 1.3 equiv.) in THF (54 mL) at 0 °C was added a solution of potassium tert-butoxide (3.02 g, 26.89 mmol, 1.3 equiv.) in THF (26 mL) dropwise. The flask was rinsed with 2 x 1 mL of THF to ensure complete transfer.
After stirring at room temperature for 10 minutes, the solution was cooled to 0 °C and a solution of 3-(cyclopentyloxy)-4-methoxybenzaldehyde (4.56 g, 20.7 mmol, 1.0 equiv.) in THF (10 mL) was added dropwise. The flask was rinsed with 3 x 2 mL of THF to ensure complete transfer.
The resultant mixture was stirred at room temperature for 16 hours. After concentration in vacuo, the crude material was purified by column chromatography (10% ethyl acetate/hexanes) to afford 13 (4.48 g, 20.5 mmol, 99%) a yellow oil.