a
Department of Chemistry, Virginia Commonwealth University, 1001 West Main Street, Richmond, VA 23284-3028, USA
› Author AffiliationsStartup funding was provided by the Virginia Commonwealth University and the Bill and Melinda Gates Foundation (The Medicines for All Institute, grant number OPP1176590)
Dedicated to Professor Barry Trost in honor of his 80th 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.
3a
Dumrath A,
Lubbe C,
Beller M.
In Palladium-Catalyzed Coupling Reactions: Practical Aspects and Future Developments.
Molnar A.
Wiley-VCH; Weinheim: 2013: 445
10Biphenyl-4,4′-dicarbaldehyde (14a); Typical HC Procedure
A crimp-cap vial equipped with magnetic stirrer bar was charged with (dppf)PdCl2·CH2Cl2 (8.2 mg, 0.010 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 white solid; yield: 53.2 mg (77%); mp 141–143 °C; Rf = 0.26 (25% EtOAc–hexanes).
1H NMR (600 MHz, CDCl3): δ = 10.09 (s, 2 H), 8.00 (d, J = 8.0 Hz, 4 H), 7.80 (d, J = 8.0 Hz, 4 H). 13C NMR (CDCl3, 150 MHz): δ = 191.7, 145.5, 135.9, 130.4, 128.0. HRMS (DART): m/z [M + H]+ calcd for C14H11O2: 211.0759; found: 211.0788.
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:
14a
Giovannini R,
Knochel P.
J. Am. Chem. Soc. 1998; 120: 11186
162′,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%); Rf = 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.
17a
Patel ND,
Sieber JD,
Tcyrulnikov S,
Simmons BJ,
Rivalti D,
Duvvuri K,
Zhang Y,
Gao DA,
Fandrick KR,
Haddad N,
Lao KS,
Mangunuru HP. R,
Biswas S,
Qu B,
Grinberg N,
Pennino S,
Lee H,
Song JJ,
Gupton B F,
Garg NK,
Kozlowski MC,
Senanayake CH.
ACS Catal. 2018; 8: 10190
