1,5-Double-Carboxylation of 2-Alkylheteroarenes Mediated by a Combined Brønsted Base System

Abstract

This paper reports that a combined Brønsted base (t-BuOLi/CsF or LiOCEt₃/CsF) system mediates the 1,5-double-carboxylation of nonfused 2-alkylhetarenes at both the benzylic and δ-positions. A wide range of functional groups (OMe, F, Cl, CF₃, OCF₃, sulfide, CN, amide, ketone, or sulfone) are tolerated under the established reaction conditions.

Key words

carboxylation - Brønsted bases - alkylhetarenes - CO₂ fixation - C–H bond functionalization

Publication History

Received: 10 November 2022

Accepted after revision: 30 November 2022

Accepted Manuscript online:
30 November 2022

Article published online:
19 December 2022

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• 9 Mita, Sato, and co-workers reported that palladium catalyzes the 1,5-double-carboxylations of 2-hetarylmethyl acetates (pyrrole and furan derivatives) with ZnEt₂ (see ref. 6c).
• 10 The results obtained in the reactions of 1a conducted at 160 °C and 140 °C show a predominant occurrence of the first carboxylation at the benzylic position (formation of 3 and 4) over that at the C-5 position (formation of 5) (Table 1, entries 4 and 11, respectively).
• 11 The use of LiOCEt₃ also provided 2a in an isolated high yield (86%); however, in this study, commercially available t-BuOLi was used as a standard base.
• 12 1,2-Dimethyl-3-phenyl-1H-pyrrole was also tested as a substrate, but gave the dicarboxylated product in a trace amount (result not shown).
• 13 Under CO₂ atmosphere, equilibrium between the tert-butoxide base and carbonate base exists and is mainly shifted to the latter side.¹⁶ When 1a was treated with t-BuO₂COLi and CsF under an Ar atmosphere, 2a was obtained in 80% yield (see Supplementary Information; Scheme S1).
• 14 Mita, Sato, and co-workers proposed a C5-carboxylation mechanism relevant to that of Path a in Scheme 4 for the double-carboxylation of 2-hetarylmethyl acetates; in their scheme, oxidative addition of the substrate onto a palladium complex occurs to form a (π-allyl)palladium species, with subsequent nucleophilic carboxylation at the C-5 position (see ref. 6c).
• 15 Methyl 5-(2-methoxy-2-oxoethyl)-4-phenylthiophene-2-carboxylate (2a): Typical Procedure In a glove box under an Ar atmosphere, a solution of 1a (35.7 mg, 0.205 mmol), CsF (153.1 mg, 1.008 mmol), and t-BuOLi (81.1 mg, 1.013 mmol) in DMI (1.0 mL) was prepared in an oven-dried glass tube (φ = 1.65 cm, 10.5 cm) equipped with a stirrer bar. The tube was sealed with a rubber cap and removed from the glove box. The tube was then evacuated and refilled with CO₂ gas, and this procedure was repeated three times. The tube was further flushed with CO₂ gas for 5 min with stirring at rt. The rubber cap was then replaced with a cap containing an inner Teflon film, and the mixture was stirred at 180 °C for 13 h. 1 M aq HCl (2 mL) was then added at 0 °C, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were collected, washed with H₂O (10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated. A solution of the residue in MeOH (1.0 mL) was treated with a 0.6 M solution of TMSCHN₂ in hexane (2.0 mL, 1.2 mmol) at 0 °C, and the mixture was stirred stirring at rt for 15 min. The mixture was then concentrated and the crude product was purified by column chromatography [silica gel, hexane–EtOAc (5:1)] to give a white solid; yield: 52.4 mg (0.180 mmol, 88%); mp 69–71 ℃ (hexane–EtOAc). IR (neat): 3072, 2955, 1711, 1440, 1264, 748, 704 cm^–1. ¹H NMR (600 MHz, CDCl₃/TMS): δ = 7.74 (s, 1 H), 7.43 (t, J = 7.5 Hz, 2 H), 7.39–7.34 (m, 3 H), 3.89 (s, 3 H), 3.86 (s, 2 H), 3.73 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 34.2, 52.1, 52.4, 127.7, 128.65, 128.67, 131.4, 134.91, 134.93, 137.2, 141.9, 162.4, 170.3. LRMS (EI): m/z = 290 (M⁺). HRMS (EI-TOF): m/z [M⁺] calcd for C₁₅H₁₄O₄S: 290.0613; found: 290.0602.
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