Organocatalytic asymmetric chlorinative dearomatization of naphthols

A highly enantioselective chlorinative dearomatization of 1-naphthol and 2-naphthols was realized for the first time, providing chiral naphthalenones with a Cl-containing all-substituted stereocenter in excellent yields and enantioselectivity (up to 97% yield and 96% ee).


General considerations
Unless stated otherwise, all solvents were purified and dried according to standard methods prior to use. 1 H and 19 F NMR spectra were recorded on Varian or Angilent instrument (400 MHz and 376 MHz, 300 MHz and 282 MHz, respectively) and referenced relative to tetramethylsilane signal or residual protio solvent signals and CFCl 3 respectively. 13 C NMR spectra were recorded on Varian or Angilent instrument (100 MHz or 75 MHz) and referenced relative to residual solvent signals. Data for 1 H NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet or unresolved, br = broad singlet, coupling constant(s) in Hz, integration). Data for 13 C NMR and 19 F NMR are reported in terms of chemical shift (δ, ppm).

General procedure for preparation of 1f-1h, 1k
To a 25 mL two-neck round-bottomed flask equipped with a condenser, methyl 6-bromo-2-hydroxy-1-naphthoate (562 mg, 2.0 mmol), boronic acid (3.0 mmol), (i-Pr) 2 NH (202 mg, 2.0 mmol), Pd(OAc) 2 (9.0 mg, 0.04 mmol) and H 2 O (4.0 mL) were added successively. The mixture was reacted at 100 o C until the reaction was complete (monitored by TLC). The mixture was filtered through a pad of celite and washed with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/50, v/v) to afford the product.
The reaction mixture was stirred at 70 o C until the reaction was complete (monitored by TLC). The mixture was filtered through a pad of celite, washed with ethyl acetate, and followed by concentration. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/20, v/v) to afford the product.

General procedure for asymmetric chlorination of naphthols
To a Schlenk tube, DCDMH (70.9 mg, 0.36 mmol), (DHQD) 2 PHAL (23.4 mg, 0.03 mmol) and toluene (2.0 mL) were added. After stirred for 10 min at -78 o C, 1 (0.3 mmol) was added in one portion. After the reaction was complete (monitored by TLC), the reaction was quenched by the addition of saturated Na 2 SO 3 aqueous solution (3.0 mL). The organic layer was extracted with ethyl acetate, washed with brine, dried over Na 2 SO 4 , filtered and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/20, v/v) to afford the product.

Mechanistic Investigations
Then the reaction mixture was stirred at -78 o C until the reaction was complete (monitored by TLC). The reaction was quenched by the addition of saturated Na 2 SO 3 aqueous solution (3.0 mL). The organic layer was extracted with ethyl acetate, washed with brine, dried over Na 2 SO 4 , filtered and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 1/20, v/v) to afford the product 2a (65.8 mg, 93% yield, 64% ee).

Crystal data
In order to determine the absolute configuration of the products, the crystal of enantiopure 2d was obtained by slow evaporation in hexane and EA and a single crystal X-ray analysis determined its configuration as R (Fig. 1) (12) Extinction coefficient 0.0013 (14) Largest diff. peak and hole 0.530 and -0.519 e.A^-3 In order to determine the absolute configuration of 2t, the crystal of enantiopure 2t was obtained by slow evaporation in hexane and Et 2 O and a single crystal X-ray analysis determined its configuration as R (Fig. 2) (CCDC 1048128).