Identification of a Surprising Boronic Acid Homocoupling Process in Suzuki–Miyaura Cross-Coupling Reactions Utilizing a Hindered Fluorinated Arene

Samantha L. Gargaro; Bre'Shon Dunson; Joshua D. Sieber

doi:10.1055/s-0040-1707266

Synlett, Table of Contents

Synlett 2021; 32(05): 511-516
DOI: 10.1055/s-0040-1707266

cluster

The Power of Transition Metals: An Unending Well-Spring of New Reactivity

Identification of a Surprising Boronic Acid Homocoupling Process in Suzuki–Miyaura Cross-Coupling Reactions Utilizing a Hindered Fluorinated Arene

Samantha L. Gargaro

^aDepartment of Chemistry, Virginia Commonwealth University, 1001 West Main Street, Richmond, VA 23284-3028, USA

,

Bre'Shon Dunson

^aDepartment of Chemistry, Virginia Commonwealth University, 1001 West Main Street, Richmond, VA 23284-3028, USA

^bThomas Jefferson High School, 4100 W Grace Street, Richmond, VA 23230, USA

,

Joshua D. Sieber

^aDepartment of Chemistry, Virginia Commonwealth University, 1001 West Main Street, Richmond, VA 23284-3028, USA

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Abstract

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Dedicated to Professor Barry Trost in honor of his 80^th birthday.

Abstract

The Suzuki–Miyaura cross-coupling reaction of 2-bromo-1,3-bis(trifluoromethyl)benzene with arylboronic acids was evaluated and determined to suffer from the formation of large amounts of boronic acid homocoupling products in conjunction with dehalogenation. Homocoupling product formation in this process likely occurs through a rare protonolysis/second transmetalation event rather than by the well-established mechanism requiring the involvement of O₂. The scope of this boronic acid homocoupling reaction was investigated and shown to predominate with electron-deficient arylboronic acids. Finally, a good yield of cross-coupling products could be obtained by employing dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (SPhos) as the ligand.

Key words

palladium catalysis - Suzuki–Miyaura reaction - cross-coupling - arylboronic acids - bromobistrifluoromethylbenzene

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References

References and Notes

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13 The results obtained are also consistent with the formation of HC product 14a from 21 through a bimetallic-catalyst-exchange mechanism where aryl–aryl exchange between two molecules of 18 occurs to generate 21 along with a symmetrical Pd complex bearing two 2,6-bis(trifluoromethyl)phenyl fragments that would need to undergo protonolysis to form 9 and reenter the catalytic cycle. For an example of bimetallic exchange, see: Wang D., Izawa Y., Stahl S. S.; J. Am. Chem. Soc.; 2014, 136: 9914

Other strategies to facilitate reductive elimination using electron-deficient fluorinated styrenes as additives have been reported. It is possible that coordination of electron-deficient arene 9 to the Pd-intermediates involved in these processes might play a role in the observed reaction outcomes. For examples, see:

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15 See the Supporting Information.
16 2′,6′-Bis(trifluoromethyl)biphenyl-4-carbaldehyde (13a): Typical CC Procedure A crimp-cap vial equipped with magnetic stirrer bar was charged with Pd(OAc)₂ (2.2 mg, 0.010 mmol), SPhos (8.3 mg, 0.020 mmol), (4-formylphenyl)boronic acid (2a; 97.9 mg, 0.653 mmol), Na₂CO₃ (69.2 mg, 0.653 mmol), and 2-bromo-1,3-bis(trifluoromethyl)benzene (6; 95.7 mg, 0.327 mmol). The vial was sealed with a crimp-cap septum and filled with Ar by using three vacuum–purge cycles. Degassed (Ar sparge) 1,4-dioxane (0.70 mL) and H₂O (0.25 mL) were added, and the vial was immersed in an oil bath at 90 °C for 2 h, then cooled to r.t. H₂O was added, and the mixture was extracted with CH₂Cl₂ (2 × 4 mL). The combined organics were mixed with PhCF₃ (60.0 μL, 0.488 mmol) as an added standard, and an aliquot was diluted in CDCl₃ for quantitative ¹⁹F NMR spectroscopy. The organics were then dried (Na₂SO₄) and concentrated in vacuo. Purification by flash chromatography [silica gel, hexanes–EtOAc (0–25%)] gave a yellow oil; yield: 84.6 mg (85%); R_f = 0.59 (25% EtOAc–hexanes). ¹H NMR (600 MHz, CDCl₃): δ = 10.09 (s, 1 H), 7.99 (d, J = 8.0 Hz, 2 H), 7.91 (d, J = 8.0 Hz, 2 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 2 H). ¹³C NMR (150 MHz, CDCl₃): δ = 191.8, 140.3, 138.7, 136.1, 130.9 (q, J = 30.0 Hz), 130.8, 129.4 (q, J = 5.0 Hz), 128.5, 128.2, 123.1 (q, J = 275.0 Hz). ¹⁹F NMR (565 MHz, CDCl₃): δ = –57.5. HRMS (DART): m/z [M + H]⁺ calcd for C₁₅H₉F₆O: 319.0558; found: 319.0578.

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Supplementary Material

Supporting Information