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Synlett 2002(12): 1976-1982
DOI: 10.1055/s-2002-35587
LETTER
© Georg Thieme Verlag Stuttgart · New York

Regioselective Synthesis of 4-Substituted-1-Aryl-1-butanones Using a Sonogashira-Hydration Strategy: Copper-Free Palladium-Catalyzed Reaction of Terminal Alkynes with Aryl Bromides [1]

Manojit Pal*, Karuppasamy Parasuraman, Shalabh Gupta, Koteswar Rao Yeleswarapu
Chemistry-Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500050, India
Fax: +91(40)3045438 ; e-Mail: manojitpal@drreddys.com;
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Publication History

Received 11 October 2002
Publication Date:
20 November 2002 (online)

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Abstract

A simple one-pot procedure has been developed for the synthesis of 4-substituted-1-aryl-1-butanones through copper-free Sonogashira reaction of aryl bromides with terminal alkynes in DMF under inert atmosphere, followed by the treatment with acid in the presence of oxygen. A variety of aryl bromides was reacted with 3-butyn-1-ol according to this procedure to give the expected compounds in good yield. The mechanism of the reaction and applications of the methodology are discussed.

Key words

1-aryl-1-butanones - aryl bromide - 3-butyn-1-ol - palladium catalyst - hydration

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DRL Publication No. 251

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DRL Publication No. 251

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Dimerization of terminal alkyne in the presence of copper(I) salt and amine base is a required process for
the in situ conversion of Pd(II) to the active catalyst Pd(0), see ref. 16a.

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Typical procedure for the synthesis of 4-substituted 1-aryl-1-butanones: Preparation of Ia: To a solution of 4-bromoacetophenone (1 g, 5.03 mmol) in DMF (10mL) was added PdCl2(PPh3)2 (0.10 g, 0.15 mmol)and Et3N (4.06 g, 40.20 mmol) under nitrogen atmosphere. The mixture was stirred for 15 min at 25 C and then 3-butyn-1-ol (0.71 g, 10.05 mmol) was added very slowly via syringe to the stirred reaction mixture. The temperature of the mixture was increased slowly to 80 °C and stirring continued for 8 h. During the reaction, which was followed by TLC, precipitation of Et3N·HBr as crystalline solid was observed. After the complete consumption of the aryl bromide, the reaction mixture was cooled to r.t. and 20% HCl solution (100 mL) was added to it with vigorous stirring. After stirring for 8 h the mixture was diluted with water and EtOAc (150 mL), filtered through a small pad of celite (EtOAc). The organic layer was collected, washed with H2O (2 × 100 mL), dried over anhyd Na2SO4, filtered and concentrated under low vacuum. The residue thus obtained was purified by flash chromatography to afford the desired compound. Compound Ia was isolated in 59% yield as light yellow solid, mp 91-92 °C (hexane); IR (KBr): 3342 (br, OH), 1678 (C=O), 1502 cm-1; 1H NMR (200 MHz, CDCl3): δ = 8.04 (m, 4 H, ArH), 3.76 (t, J = 5.91 Hz, 2 H, CH 2OH), 3.16 (t, J = 6.98 Hz, 2 H, CH2CO), 2.65 (s, 3 H, CH3), 2.09-1.97 (m, 2 H, CH2), 1.65 (br s, D2O exchangeable, 1 H, OH); M (CI, I-butane): m/z (%) = 207 (100) [MH+]; 13C NMR: 199.89, 197.61, 139.94, 139.87, 128.37 (2 C), 128.13 (2 C), 61.71, 35.42, 26.74, 26.62.
Spectral data for 1d: pale yellow oil; IR (KBr): 3420 (br, OH), 1679 (C=O), 1607 cm-1; 1H NMR (200 MHz, CDCl3): δ = 7.90 (d, J = 7.81 Hz, 2 H, ArH), 7.29 (d, J = 7.80 Hz,
2 H, ArH), 3.76 (t, J = 5.86 Hz, 2 H, CH 2OH), 3.13 (t, J = 6.84 Hz, 2 H, CH2CO), 2.43 (s, 3 H, CH3), 2.09-1.97
(m, 2 H, CH2), 1.80 (br s, D2O exchangeable, 1 H, OH); MS (CI, I-butane): m/z (%) = 179 (100) [MH+]; 13C NMR: 199.12, 143.87, 134.27, 129.20 (2 C), 128.15 (2 C), 62.28, 35.21, 27.00, 21.64.
Spectral data for 1ff: IR (KBr): 1719 (OCHO), 1665 (C=O), 1588 cm-1; 1H NMR (200 MHz, CDCl3): δ = 8.07 (s, 1 H, CHO), 7.88 (d, J = 8.33 Hz, 2 H, ArH), 7.27 (d, J = 8.30 Hz, 2 H, ArH), 4.28 (t, J = 6.31 Hz, 2 H, CH2O), 3.05 (t, J = 7.13 Hz, 2 H, CH2CO), 2.53 (s, 3 H, SCH3), 2.16-2.09 (m, 2 H, CH2); MS (CI, I-butane): m/z (%) = 239 (100) [MH+].