Ring Expansion of 1-Indanones to 2-Halo-1-naphthols as an Entry Point to Gilvocarcin Natural Products

Herein, we describe a two-step ring expansion of 1-indanones to afford 2-chloro/bromo-1-naphthols (32 examples). The developed method shows broad functional group tolerance, benefits from mild reaction conditions, and enables rapid access to the tetracyclic core of gilvocarcin natural products. The orthogonally functionalized products allow for selective postmodifications as exemplified in the total synthesis of defucogilvocarcin M. For the selective oxidation of the chromene, a mild and regioselective oxidation protocol (DDQ and TBHP) was developed.

a 2.2 equivalents of Cl-source and 2.0 equivalents of base were used. b " aq. HCl" = 4 M HCl, 40 min, 23 °C. "TBAF" = 1.1 eq TBAF (1 M in THF), 30 min, 23 °C. c These conditions were preferred over the conditions from Entry 5 for substrate compatibility of a broader scope. a) Base was added at 23 °C. CHBr3 was added at the temperature given in the table with subsequent warming to 23 °C. b) Base was added at -78 °C. CHBr3 was added at -78 °C with subsequent warming to 23 °C. c) We want to annotate, that the TBS-protection of 1-indanones is highly sensitive to the used amount of the solvent (benzene) with slightly higher dilutions already leading to significantly lower conversion, even after extended reaction times. d) Repeating this reaction revealed a limited reproducibility of the yield. The best yield is given in the table. For detailed information, see text. e) Repeating this reaction revealed a reliable reproducibility of the yield.

General Procedures General Procedure Towards 2-Chloronaphthols (Procedure A)
Triethylamine (158 µL, 1.13 mmol, 1.50 equiv) and trimethylsilyl chloride (145 µL, 1.13 mmol, 1.50 equiv) were added in sequence to a suspension of sodium iodide (11.3 mg, 75.7 µmol, 10 mol%) and indanone (757 µmol, 1 equiv) in acetonitrile (910 µL, 0.83 M) at 0 ˚C. The resulting suspension was allowed to warm to 23 ˚C and stirred for 16 hours. After removal of the solvent under reduced pressure, the residue was dissolved in n-hexane (5 mL) and the suspension was filtered through a short plug of Celite ® . The filtrate was then concentrated under reduced pressure to afford the crude silyl enol ether.
This material was used immediately without further purification.
The crude silyl enol ether was dissolved in pentane (900 µL, 0.84 M), cooled to -78 °C and slowly added to a suspension of potassium tert-butoxide (sublimed grade, 170 mg, 1.51 mmol, 2.00 equiv) in pentane (1.51 mL, 1 M) at -78 ˚C. The flask of the crude silyl enol ether was rinsed for three times with pentane (3 × 800 µL) and added to the reaction in the same fashion. A solution of chloroform (133 µL, 1.67 mmol, 2.20 equiv) in pentane (1.67 mL, 1 M) was added dropwise to the mixture and the suspension was stirred at -78 ˚C for 30 minutes before allowing to warm to 23 ˚C. After stirring for 1.5 hours, water (2 mL) was added to the reaction mixture and the resulting solution was concentrated to 4 mL under reduced pressure. Tetrabutylammonium fluoride trihydrate (358 mg, 1.13 mmol, 1.50 equiv) was added in one portion and the solution was stirred vigorously for 40 minutes. Aqueous hydrochloric acid (1 M, 5 mL) was added and the resulting solution was extracted with ethyl acetate (3 × 10 mL). The organic layer was then washed with water (2 × 10 mL) and a saturated aqueous solution of sodium chloride (10 mL) and the washed solution was dried over magnesium sulfate. Filtration of the dried solution followed by concentration under reduced pressure gave the crude product, which was purified by silica gel chromatography to give the desired 2-chloronaphthols.
Reaction progress was visualized by basic Al2O3-TLC-monitoring. If remaining starting material was indicated after two hours of stirring, additional triethylamine (199 µL, 1.43 mmol, 3.40 equiv) and triisopropylsilyl trifluoromethanesulfonate (158 µL, 588 µmol, 1.40 equiv) were added and stirred until full conversion (only needed for substrate 24-Br in our hands). The mixture was diluted with cyclohexane (5 mL), filtered through a short plug of silica and the filtrate was concentrated under reduced pressure at 23 °C. The crude silyl enol ether was used immediately without further purification.
The crude silyl enol ether was dissolved in n-hexane (600 µL, 0.7 M), cooled to -78 °C and added to a suspension of potassium tert-butoxide (sublimed grade, 212 mg, 1.89 mmol, 4.50 equiv) in n-hexane (859 µL, 2.2 M) at -78 ˚C. The flask of the crude silyl enol ether was rinsed with n-hexane (3 × 500 µL) and added to the reaction in the same fashion. After 20 minutes, a solution of freshly distilled bromoform (73.0 µL, 840 µmol, 2.00 equiv) in n-hexane (859 µL, 2.2 M) was added dropwise at -78 ˚C and stirred at that temperature for one hour. The reaction was then warmed to 23 °C within one hour and stirred for an additional hour. The solvent was removed under reduced pressure to give the crude silylated 2bromonaphthol, which was dissolved in N,N-dimethylformamide-water (20:1, 1.68 mL, 0.25 M).
Potassium acetate (41.0 mg, 420 µmol, 1.00 equiv) was added and the reaction was stirred for one hour at 23 ˚C. If silica-TLC-monitoring indicated remaining starting material after 1.5 hours, additional potassium acetate (41.0 mg, 420 µmol, 1.00 equiv) was added and the reaction mixture was stirred at 45 °C until full conversion (only needed for substrates 27-Br and 28-Br in our hands). Water (4 mL) was added to the reaction mixture and the resulting solution was extracted with diethyl ether (6 × 4 mL).
The combined organic layers were washed with water (8 mL) and a saturated aqueous solution of sodium chloride (8 mL) and the washed solution was dried over magnesium sulfate. The dried solution was filtered and the filtrate was concentrated under reduced pressure. Purification by silica gel chromatography gave the desired 2-bromonaphthols.
The mixture was diluted with 30 mL of cyclohexane, filtered through a short plug of silica and the filtrate was evaporated under reduced pressure at 23 °C to afford the crude silyl enol ether. This material was used immediately without further purification.

NOTE: Addition of triphenylphosphine prior to tetrabromomethane led to significant dimerization of S5
forming the corresponding dibenzylether (not shown).  1, 141.3, 139.0, 122.1, 112.5, 108.9, 65.8, 56.8, 21.9.  The mixture was allowed to cool to 23 °C and diluted with a solution of lithium chloride (4 M, 5 mL) and then extracted with ethyl acetate (3 × 30). The combined organic layers were washed with a saturated aqueous solution of sodium chloride (40 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was evaporated under reduced pressure to give the crude product. Purification was performed by silica gel chromatography (33 % dichloromethane in cyclohexane) to afford quinone 39-Br (223 mg, 400 µmol, 78%) as a yellow foam, accompanied by recovered benzyl bromide 38-Br (21.0 mg, 71.4 µmol, 14%).

Optimization Studies for the anticipated Stille-Kelly coupling
All solids (dihalogen 40, palladium catalyst and additives) were placed into a 20-mL-pressure tube in a glove box. All liquids (solvent and stannane) were added outside of the glove box via canula under an argon counterflow. The pressure tube was sealed with a Teflon® screw-cap and then put into a preheated oil bath under light exclusion. After the given reaction time, the oil bath was removed to allow the reaction to cool to 23 °C.
For reactions using DMF or NMP as solvent (Entries 7, 20, 28 and 29): The mixture was diluted with a solution of lithium chloride (4 M, 5 mL) and then extracted with ethyl acetate (3 × 10). The combined organic layers were washed with a saturated aqueous solution of sodium chloride (10 mL) and the washed solution was dried over magnesium sulfate. The dried solution was filtered and the filtrate was evaporated under reduced pressure to give the crude product.

Meta-functionalization of 2-Bromo-5-iodo-1-naphthol
Treatment of 2-bromo-5-iodonaphthol 22-Br with N-chlorosuccinimide (NCS) in acetonitrile affords quantitative conversion to bench-stable enone 47. The succinimide could be removed by filtration of 47 through a short plug of silica with only little decomposition (less than 10%), while aqueous basic workup results in partial decomposition accompanied with significant enolization. Interestingly, in a first attempt the use of Nagata's reagent led to nucleophilic attack of mainly the ethyl group (40%) and only minor amounts of the cyanide (25%), while in any other attempt to reproduce this result the cyanide S8-CN was isolated as main product (Entry 1). Similarly, AlEt3 underwent conjugate addition in 85% overall (Entry 2), while a one-pot transformation starting from naphthol 22-Br showed almost quantitative overall yield (Entry 5). The use of SnCl4 allowed for the application of Mukaiyama-Aldol conditions (Entry 3) as well as for the installation of nonactivated anisole (Entry 4). It is noteworthy, that both products have been isolated as a mixture of 2-chloro-and 2-bromonaphthols, indicating a SnCl4-induced halogen shuffle. For all entries, naphthol 22 was isolated as minor side-product (between 3 and 15%). Since several of the known stable phenols and naphthols in their keto-form are decorated with halogens (especially in the ortho-position) [4] we conclude that the bromine and the iodine might contribute to the stability of the dienone-form 47 by their electronegativity. However, similar dearomatization reactions are known for less-substituted systems (compare reference 24a).
After two hours of stirring at that temperature, the residual solid dry-ice was removed from the external acetone bath to initiate slow warming to 23 °C within 50 minutes. After stirring for ten minutes at 23 °C, the red solution was diluted with water (3 mL) and extracted with diethyl ether (3 × 5 mL). The combined organic layers were washed with a saturated aqueous solution of sodium chloride (5 mL) and the washed solution was dried over magnesium sulfate. The dried solution was filtered and the filtrate was concentrated under reduced pressure to give a crude mixture containing 9% of S8-Et and 63% of presumably S9-CN as indicated by internal-standard-1 H-NMR. Purification by silica gel chromatography (11% ethyl acetate in cyclohexane + 2% acetic acid) afforded compound S8-Et (3.50 mg, 9.20