Coumarins by Direct Annulation: β‐Borylacrylates as Ambiphilic C3‐Synthons

Abstract Modular β‐borylacrylates have been validated as programmable, ambiphilic C3‐synthons in the cascade annulation of 2‐halo‐phenol derivatives to generate structurally and electronically diverse coumarins. Key to this [3+3] disconnection is the BPin unit which serves a dual purpose as both a traceless linker for C(sp2)–C(sp2) coupling, and as a chromophore extension to enable inversion of the alkene geometry via selective energy transfer catalysis. Mild isomerisation is a pre‐condition to access 3‐substituted coumarins and provides a handle for divergence. The method is showcased in the synthesis of representative natural products that contain this venerable chemotype. Facile entry into π‐expanded estrone derivatives modified at the A‐ring is disclosed to demonstrate the potential of the method in bioassay development or in drug repurposing.

to ambient temperature and stirred for an additional 10 h. After the addition of Et 2 O (1 mL), the formed precipitate was filtered off and dried under reduced pressure. The crude product was dissolved in MeOH (2 mL) before the addition of Boc 2 O (262 mg, 1.2 mmol, 1.2 eq.) and NEt 3 (415 L, 303 mg, 3.0 mmol, 3.0 eq.). The reaction mixture was stirred at ambient temperature for 24 h. After the reaction was complete, the mixture was adjusted to pH = 3 by the addition of HCl (1 M) and organics were extracted with EtOAc (3x10 mL). The combined organics were dried over MgSO 4 and the solvent was evaporated under reduced pressure. The crude residue was purified by column chromatography (SiO 2 , 30% EtOAc/n-pentane) to give the desired product as a colourless solid (269 mg, 71%).   24 = 24.023.
Analytical data in agreement with literature data. [4] Bromination of estrone Estrone (811 mg, 3.0 mmol, 1.0 eq.) was dissolved in CHCl 3 (20 mL) and N-bromosuccinimide (588 mg, 3.3 mmol, 1.1 eq.) was added. The mixture was heated to 70 °C with stirring for 6 h. After cooling to ambient temperature, EtOAc (50 mL) was added and the organic layer was washed with brine (20 mL), dried over MgSO 4 and the solvent was evaporated under reduced pressure. The crude residue was purified by column chromatography (SiO 2 , 2% to 10% EtOAc/n-pentane) to give several regioisomers.

Synthesis of 2-bromo-3-((tert-butyldimethylsilyl)oxy)-4-methoxybenzaldehyde (S9)
According to a procedure by Schäfer et al. [5] , 3-hydroxy-4-methoxybenzaldehyde (1. atmosphere. Subsequently, a solution of Br 2 (1.3 g, 0.42 mL, 8.4 mmol, 1.05 eq.) in acetic acid (2mL) was added dropwise and the mixture was stirred at ambient temperature for 1 h before it was poured into ice-water (20 mL). The formed precipitate was filtered-off, washed with ice-cold water and dried under reduced pressure. The crude product was dissolved in DMF (80 mL), placed under an argon atmosphere and cooled to 0 °C before the addition of N,N-Diisopropylethylamine (4.1 mL, 3.1 g, 24.0 mmol, 3.0 eq.). The reaction mixture was stirred for 15 min at 0 °C before the addition of TBDMSCl (1.4 g, 9.6 mmol, 1.2 eq.) in small portions. The mixture was warmed to ambient temperature and was stirred for an additional 2 h. The reaction was quenched by the addition of water (50 mL) and organics were extracted with EtOAc (3 x 120 mL). The combined organic layers were dried over MgSO 4 and the solvent was evaporated under reduced pressure. The crude residue was purified by column chromatography (SiO 2 , 0% to 10% EtOAc/n-pentane) to give the desired product as a colorless oil (1.59 g, 58%). Analytical data in agreement with literature. [5] Synthesis of 5-(bromomethyl)-1,2,3-trimethoxybenzene (S10) To a solution of 3,4,5-trimetoxybenzylic alcohol (594.7 mg, 3.0 mmol, 1.0 eq.) and CBr 4 (1.04 g, 3.15 mmol, 1.05 eq.) in DCM (0.2 M, 15 mL), PPh 3 (856 mg, 3.3 mmol, 1.1 eq.) was added in small portions. The reaction mixture was stirred at ambient temperature for 1 h before the solvent was evaporated under reduced pressure. The crude residue was purified by column chromatography (SiO 2 , 10% EtOAc/n-pentane) to give the desired product as a white solid (590 mg, 75%).  Analytical data in agreement with literature. [6] Synthesis of triphenyl(3,4,5-trimethoxybenzyl)phosphonium bromide (S11) To a solution of PPh 3 (526.0 mg, 2.1 mmol, 1.05 eq.) in toluene (0.3 M, 7 mL), S10 (522.0 mg, 2.0 mmol, 1.0 eq.) was added. The mixture was stirred at 110 °C for 6 h. After the reaction was complete the mixture was cooled to 0 °C and the formed precipitate was filtered-off and washed with ice-cold toluene. The residue was dried under reduced pressure to give the desired product as a colorless solid (879.0 mg, 84%).  Analytical data in agreement with literature. [6]
The solvent was evaporated under reduced pressure and the crude residue was purified by column chromatography (SiO 2 , 5% EtOAc/n-pentane) to give the desired product as a pink solid (428.9 mg, 29%).  Analytical data in agreement with literature. [9] Synthesis of 5-bromobenzofuran-4-ol (S17) S16 (293.9 mg, 1.0 mmol, 1.0 eq.) was dissolved in MeCN (7 mL) and the solution was cooled to 0°C before the addition of DBU (240 µL, 1.6 mmol, 1.6 eq.). The mixture was allowed to warm up to ambient temperature and was stirred for additional 16 h. After completion, the reaction was quenched by sat. aq. NH 4 Cl (5 mL) and organics were extracted with DCM (3 x 25 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO 4 and the solvent was evaporated under reduced pressure. The crude residue was purified by column chromatography (15% Et 2 O/n-pentane) to give the desired product as a white solid (164.9 mg, 77%).

General Procedure A: Alkyne deprotonation and nucleophilic addition to ethyl chloroformate
According to a procedure by Shindo et al. [10] an oven dried flask was purged with argon before the addition of alkyne (1.0 eq.) and dry THF (0.2 M). The solution was cooled to -78 °C and n-BuLi (1.1 eq.) was added. The solution was stirred for 1 h before the addition of ethyl chloroformate (1.1 eq.). The reaction mixture was stirred and allowed to warm to ambient temperature overnight. After subsequent quenching of the reaction by addition of sat. aq. NH 4 Cl, the organics were extracted with Et 2 O (3x). The combined organic layers were dried over MgSO 4 and the solvent was evaporated under reduced pressure. The crude residue was purified by column chromatography (SiO 2 , specified combination of solvents).
R f = 0.63 (EtOAc/n-pentane 1:9). Analytical data in agreement with literature data. [13] General Procedure B: Copper-catalyzed borylation of alkynes According to a procedure by Santos et al. [14] a flask was equipped with the corresponding alkyne (1.0 eq.), CuSO 4 (5 mol%), 4-methylpyridine (0.25 eq.) and B 2 pin 2 (0.75 eq.). Water (1.0 M) was added and the mixture was stirred at 50 °C for 10 min before the addition of the remaining B 2 pin 2 (0.75 eq.). The reaction was then stirred for an additional 4-16 h before it was diluted by the addition of pentane.
Organics were extracted with pentane (3x) and the combined organic layers were washed with water and dried over MgSO 4 . The solvent was evaporated at reduced pressure and the crude residue was purified by column chromatography (SiO 2 , specified combination of solvents).
The mixture was cooled and sat. aq. NaHCO 3 (200 mL) was added. The organic layer was separated and washed with sat. aq. NaHCO 3 (2 x 100 mL). The combined aqueous layers were then acidified with 37% aq. HCl, cooled to 4 °C overnight and the solid filtered to give 2,3-dibromo-2-methylbutanoic acid which was used immediately in the subsequent step. The acid was dissolved in MeOH (24 mL) and 240 mL of a 25% KOH in methanol solution was added slowly at 0 ˚C before the addition of K 2 CO 3 (4. Analytic data in agreement with literature. [15]