Microwave-Assisted Aminocarbonylation
of Aryl Bromides at Low Carbon Monoxide Pressure

Francesca Cardullo; Daniele Donati; Giancarlo Merlo; Alfredo Paio; Elena Petricci; Maurizio Taddei

doi:10.1055/s-0028-1087381

LETTER

Microwave-Assisted Aminocarbonylation of Aryl Bromides at Low Carbon Monoxide Pressure

Francesca Cardullo^a, Daniele Donati^a, Giancarlo Merlo^a, Alfredo Paio^a, Elena Petricci*^b, Maurizio Taddei^b
^a GlaxoSmithKline, Medicinal Research Centre, Via A. Fleming 4, 37135 Verona, Italy
^b Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy
Fax: +39(057)7234275; e-Mail: petricci@unisi.it;

Abstract

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Abstract

An efficient and rapid procedure for microwave-assisted aminocarbonylation of aryl bromides and iodides at low CO pressure, using (PPh₃)₂PdCl₂ or Pd(OAc)₂ as catalysts is reported. Different reaction conditions have been tested in order to carry out the reaction even on less nucleophilic anilines such as 2-chloro-4-nitroaniline, allowing a rapid access (in 20-30 min) to several diverse arylamides in good yields.

Key words

aminocarbonylation - microwave - carbon monoxide

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References

References and Notes

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All reactions were performed in a CEM Discover microwave oven equipped with a 10-mL tube for reactions under pressure (CEM Corporation). This glass vial, tested for resisting up to 250 psi (17 bar, 1723 KPa), is provided with a tube connection to an external pressure controlling system equipped with a valve and an exit tube for venting the vial at the end of the reaction. The exit tube was connected to a cylinder containing CO through a three-way connector equipped with two taps to pressurized the system before microwave irradiation.^¹³

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Surprisingly the use of an additional ligand such as 1,1-bis(diphenylphosphino)ferrocene (dppf) had a negative influence on the reaction yields.

Working at 1 atm of CO at r.t., no reaction occurred after
24 h.

General Procedure for the Synthesis of Amides 8-14:
A solution of the aryl bromide (0.46 mmol) and the amine (0.46 mmol) in anhyd THF (1.5 mL) was placed in a 10-mL tube for microwave reactions. DIPEA (240 µL, 1.38 mmol) and PdCl₂ ₍PPh₃)₂ (16 mg, 0.023 mmol) were added and the solution was submitted to pressurized CO (120 psi) and inserted in the cavity of a Discover System (CEM Corporation).^¹³,¹9 After heating for 20 min at 130 ˚C at 150 W (value previously set on the microwave oven), the tube was cooled and the internal gas pressure was released. The reaction mixture was filtered, evaporated in vacuo and the amide was purified by flash chromatography.
4-[(4-Fluorophenyl)carbonyl]morpholine (8): see ref. 30.
1-[(4-Fluorophenyl)carbonyl]-4-phenylpiperazine (9): see ref. 31.
( S )-Methyl 2-[(4-Fluorophenyl)formamido]-2-phenyl-acetate (10): ^¹H NMR (400 MHz, CDCl₃): δ = 7.56 (d, J = 5.6 Hz, 2 H), 7.36-7.42 (m, 5 H), 7.09-7.11 (m, 2 H), 5.73 (d, J = 7.2 Hz, 1 H), 3.75 (s, 3 H). ES-MS: m/z = 289 [M + 1]⁺.
4-Fluoro- N -phenylbenzamide (11): see ref. 32.
4-Ethyl- N -[(4-methoxyphenyl)methyl]benzamide (12): ^¹H NMR (400 MHz, CDCl₃): δ = 7.37 (d, J = 8.0 Hz, 2 H), 7.27-7.31 (m, 5 H), 7.04 (d, J = 8.0 Hz, 2 H), 4.54 (d, J = 5.2 Hz, 2 H), 3.77 (s, 3 H), 2.58 (q, J = 8.2 Hz, 2 H), 1.20 (q,
J = 8.2 Hz, 3 H).
4-[(4-Ethylphenyl)carbonyl]morpholine (13): see ref. 33.
2-Methoxy- N -[(4-methoxyphenyl)methyl]-5-nitrobenz-amide (14): ^¹H NMR (200 MHz, CDCl₃): δ = 8.52 (m, 2 H), 7.64 (d, J = 2.1 Hz, 1 H), 7.26 (d, J = 7.8 Hz, 2 H), 6.82 (d, J = 7.8 Hz, 2 H), 4.48 (d, J = 3.5 Hz, 2 H), 3.84 (s, 3 H), 3.75 (s, 3 H). ES-MS: m/z = 339 [M + Na]⁺.

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<A NAME="RD28908ST-26">26</A> Martinelli JR. Clark TP. Watson DA. Munday RH. Buchwald SL. Angew. Chem. Int. Ed. 2007, 46: 8460

General Procedure for the Synthesis of Amides 18-24:
A solution of 1 (0.35 mmol) and the amine (0.23 mmol) in anhyd THF (1 mL) was prepared in a 10-mL tube for microwave reactions. Anhyd Cs₂CO₃ (225 mg, 0.69 mmol) and PdCl₂ ₍PPh₃)₂ (16 mg, 0.023 mmol) were added and the solution was submitted to pressurized CO at 120 psi and heated for 30 min at 120 ˚C by microwave at 200 W (as previously described for amides 8-14). The tube was cooled and the internal gas was released. The reaction mixture was filtered, evaporated in vacuo and the crude mixture was analysed by HPLC and/or purified by flash chromatography.
4-Ethyl- N -(3-nitrophenyl)benzamide (18): ^¹H NMR (400 MHz, CDCl₃): δ = 8.45 (s, 1 H), 7.85-7.94 (m, 4 H), 7.32 (m, 1 H), 7.27 (d, J = 8.1 Hz, 2 H), 2.72 (q, J = 7.6 Hz, 2 H), 1.26 (q, J = 7.6 Hz, 3 H). ES-MS: m/z = 271 [M + 1]⁺, 293 [M + Na]⁺.
4-Ethyl- N -(2-methyl-3-nitrophenyl)benzamide (19): ^¹H NMR (400 MHz, CDCl₃): δ = 7.70-7.91 (m, 4 H), 7.29 (d, J = 8.1 Hz, 2 H), 2.72 (q, J = 7.6 Hz, 2 H), 2.33 (s, 3 H), 1.26 (q, J = 7.6 Hz, 3 H). ES-MS: m/z = 285 [M + 1].
N -(2-Chloro-5-nitrophenyl)-4-fluorobenzamide (20): see ref. 12b.
4-Fluoro- N -(2-methyl-5-nitrophenyl)benzamide (21): ^¹H NMR (400 MHz, CDCl₃): δ = 7.98-8.01 (m, 3 H), 7.41-7.52 (m, 3 H), 2.09 (s, 3 H). ES-MS: m/z = 275 [M + 1]⁺.
4-Ethyl- N -(quinolin-3-yl)benzamide (22): see ref. 34.
4-Fluoro- N -(1 H -imidazol-2-yl)benzamide (23): ^¹H NMR (400 MHz, CDCl₃): δ = 7.99 (d, J = 7.9 Hz, 2 H), 7.39 (d, J = 7.9 Hz, 2 H), 6.95 (s, 2 H). ES-MS: m/z = 228 [M + Na]⁺.
4-Ethyl- N -(1,3-thiazol-2-yl)benzamide (24): ^¹H NMR (400 MHz, CDCl₃): δ = 7.91 (d, J = 8.0 Hz, 2 H), 7.32 (d,
J = 8.0 Hz, 2 H), 7.12 (d, J = 3.6 Hz, 1 H), 6.93 (d, J = 3.6 Hz, 1 H), 2.73 (q, J = 7.6 Hz, 2 H), 1.26 (q, J = 7.6 Hz, 3 H). ES-MS: m/z = 235 [M + 1]⁺, 257 [M + Na]⁺.

N -(5-Chloro-2-nitrophenyl)-4-ethylbenzamide (17):
A solution of 1c (33 µL, 0.23 mmol) and 16 (40 mg, 0.23 mmol) in anhyd THF (1 mL) was prepared in a 10-mL tube for microwave reactions. Anhyd Cs₂CO₃ (225 mg, 0.69 mmol) and PdCl₂ ₍PPh₃)₂ (16 mg, 0.023 mmol) were added and the solution was submitted to pressurized CO at 120 psi and heated for 30 min at 120 ˚C by microwave at 200 W (as previously described for amides 8-14). The tube was cooled and the internal gas was released. The reaction mixture was filtered, evaporated in vacuo and the crude mixture was analysed by HPLC and/or purified by flash chromatography.
^¹H NMR (400 MHz, CDCl₃): δ = 11.51 (br s, 1 H), 9.13 (s, 1 H), 8.25 (d, J = 7.8 Hz, 1 H), 7.88 (d, J = 8.0 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.13 (d, J = 7.8 Hz, 1 H), 2.72 (q, J = 7.6 Hz, 2 H), 1.26 (q, J = 7.6 Hz, 3 H). ES-MS: m/z = 319 [M + 1]⁺ (^³5Cl), 321 [M + 1]⁺ (^³7Cl).

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