Brønsted‐Acid‐Catalyzed One‐Pot Synthesis of β,β‐Diaryl Esters: Direct Regioselective Approach to Diverse Arrays of 3‐Aryl‐1‐indanone Cores

Abstract

A three‐component, solvent‐dependent, Brønsted‐acid‐catalyzed reaction of benzaldehydes, silyl enolates and arene nucleophiles has been developed for the synthesis of potential drug candidate 3‐aryl‐1‐indanones. This reaction features the formation of three C−C bonds, high regioselectivity in a one‐pot strategy, broad substrate generality, facile scalability (1.04g), high functional group tolerance and viable substrates. The β‐O‐silyl ethers generated in‐situ from the Mukaiyama aldol reaction were subjected to acid‐catalyzed benzylic arylation with strong as well as weak nucleophiles, and the resultant β,β‐diaryl esters can undergo a third C−C bond formation with excellent regioselectivity through intramolecular cyclization to afford the indanone products in the same pot. Detailed mechanistic insight leads to a feasible reaction pathway. This transformation opens up a practical and adaptable approach to producing a variety of synthetically valuable transformations and enable the synthesis of medicinally valuable (R)‐tolterodine and (+)‐indatraline.

Brønsted Acid-Mediated Multicomponent One-Pot Approach to Direct Construction of 4-Aryl-hydrocoumarin Derivatives

“…Aiming to find the synthetic significance of product 5aa , we further transformed the Br- functionality into 6 using the standard Suzuki–Miyaura coupling reaction [Scheme B­(i)]. Next, we carried out sequential cyclization of 5f to synthesize polycyclic compound 7 in the presence of TfOH and HFIP [Scheme B­(ii)].…”

“…8, 137.9, 129.0, 128.8, 128.1, 127.9, 127.6, 127.4, 127.3, 126.9, 126.1, 117.0, 54.8, 42.1, 26.3, 22.6 3,3,. Compound 5d was prepared according to GP-1 with benzaldehyde 1a (1.0 equiv, 0.3 mmol, 31 μL), 2a (2.5 equiv, 152 μL, 0.75 mmol), 4d (0.45 mmol, 48 μL, 1.5 equiv), and TfOH (3.0 μL, 10 mol %) in DCE (0.5 mL) and purified by column chromatography (90:10 hexane/ethyl acetate): white solid (42 mg, 52% yield, mp 146−148 °C); 1 H NMR (400 MHz, CDCl 3 ) δ 7.24 (dt, J = 13.3, 7.0 Hz, 3H), 7.06 (d, J = 6.7 Hz, 2H), 6.97 (d, J = 7.7 Hz, 1H), 6.93 (s, 1H), 6.87 (d, J = 7.7 Hz, 1H), 3.77 (s, 1H), 2.34 (s, 3H), 1.32 (s, 3H), 1.10 (s, 3H); 13 C{ 1 H} NMR (126 MHz, CDCl 3 ) δ 173. 4, 150.6, 140.0, 138.8, 128.9, 128.8, 128.1, 127.4, 125.5, 122.7, 116.9, 54.3, 42.1, 26.2, 22.6, 21. Methyl-3,3-dimethyl-2-oxo-4-phenylchromane-6-carboxylate (5e).…”

“…, found 283.1340. Compound 5l was prepared according to GP-1 with benzaldehyde 1a (1.0 equiv, 0.3 mmol, 31 μL), 2a (2.5 equiv, 152 μL, 0.75 mmol), 4l (0.45 mmol, 50 mg, 1.5 equiv), and TfOH (3.0 μL, 10 mol %) in DCE (0.5 mL) and purified by column chromatography (80:20 hexane/ethyl acetate): light brown solid (63 mg, 79% yield, mp 167− 169 °C); 1 H NMR (500 MHz, CDCl 3 ) δ 7.29−7.19 (m, 3H), 7.05 (d, J = 6.9 Hz, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 2.6 Hz, 1H), 6.57 (dd, J = 8.3, 2.5 Hz, 1H), 5.81 (s, 1H), 3.75 (s, 1H), 1.34 (s, 3H), 1.10 (s, 3H); 13 C{ 1 H} NMR (126 MHz, CDCl 3 ) δ 174. 3, 156.2, 151.2, 140.0, 130.0, 128.9, 128.1, 127.4, 117.6, 112.3, 103.7, 53.8, 42.2, 26.2, 22.5 8, 144.2, 139.9, 138.5, 130.8, 128.9, 128.0, 127.5, 119.7, 117.8, 111.6, 54.2, 42.3, 26.2, 22.6 .…”

“…3, 156.2, 151.2, 140.0, 130.0, 128.9, 128.1, 127.4, 117.6, 112.3, 103.7, 53.8, 42.2, 26.2, 22.5 8, 144.2, 139.9, 138.5, 130.8, 128.9, 128.0, 127.5, 119.7, 117.8, 111.6, 54.2, 42.3, 26.2, 22.6 . Compound 5n was prepared according to GP-1 with benzaldehyde 1 (1.0 equiv, 0.3 mmol, 31 μL), 2a (2.5 equiv, 152 μL, 0.75 mmol), 4n (0.45 mmol, 50 mg, 1.5 equiv), and TfOH (3.0 μL, 10 mol %) in DCE (0.5 mL) and purified by column chromatography (65:35 hexane/ethyl acetate): yellow solid (63 mg, 78% yield, mp 178−180 °C); 1 H NMR (500 MHz, CDCl 3 ) δ 7.30 (d, J = 6.6 Hz, 1H), 7.28−7.20 (m, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.5 Hz, 1H), 6.60 (dd, J = 8.7, 2.7 Hz, 1H), 6.42 (d, J = 2.9 Hz, 1H), 3.69 (s, 1H), 3.55 (s, 2H), 1.35 (s, 3H), 1.11 (s, 3H); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 173. 6, 143.5, 143.2, 140.0, 128.9, 128.2, 127.5, 126.6, 117.4, 115.2, 54.9, 42.1, 26.3, 22.7; HRMS (ESI-TOF) m/z [M + H] + calcd for C 17 H 18 NO 2 268.1338268.…”

“…In this regard, we recently described the one-pot synthesis of 1-indanone through a C−C bond formation strategy. 13 Pleasingly, we design this work for the synthesis of biologically important coumarin-based scaffolds through a one-pot approach via the formation of multiple C−C and C−O bonds. Such reactions are sought because they are atomeconomical and highly conservative in terms of resources.…”