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Synlett 2009(1): 138-142  
DOI: 10.1055/s-0028-1087376
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© Georg Thieme Verlag Stuttgart ˙ New York

Oxidative Alkylation of Cyclic Benzyl Ethers with Malonates and Ketones Using Oxygen as the Terminal Oxidant

Woo-Jin Yooa, Camille A. Correiaa, Yuhua Zhangb,1, Chao-Jun Li*a
a Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, QC, H3A 2K6, Canada
Fax: +1(514)3983797; e-Mail: cj.li@mcgill.ca;
b Department of Chemistry, Tulane University, New Orleans, LA, 70118, USA
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Publication History

Received 23 September 2008
Publication Date:
12 December 2008 (online)

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Abstract

A simple oxidative alkylation of cyclic benzyl ethers with malonates and ketones was developed using a mixture of Cu(OTf)2, InCl3, and NHPI as catalyst under an atmospheric pressure of oxygen.

Key words

copper - indium - oxygen - cross-coupling - radical reactions

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1

New address: Y. Zhang, Department of Chemistry, Washington University, Campus Box 1134, One Brookings Drive, St. Louis, Missouri 63130, USA.

9

Lewis acids such as Bi(OTf)3, Yb(OTf)3, FeCl3, Co(OAc)2 were screened as co-catalysts with Cu(OTf)2. In all cases, the yields were considerably lower (<40%) compared to InCl3.

10

Representative Procedure and Spectroscopic Data - Synthesis of Dimethyl 2-(3,4-Dihydro-1 H -isochromen-1-yl)malonate (3a) In a sealable test tube equipped with a magnetic stir bar was charged Cu(OTf)2 (9.5 mg, 0.026 mmol), InCl3 (5.8 mg, 0.026 mmol), and NHPI (17.1 mg, 0.105 mmol). The reaction vessel was sealed and flushed with O2. The tube was attached to a balloon of O2 and charged with dimethyl malonate (1a) (0.060 mL, 0.524 mmol) and isochroman (2a) (0.33 mL, 2.6 mmol). The test tube was placed in an oil bath set at 55 ˚C and was allowed to stir overnight. The reaction mixture was allowed to cooled to r.t. and the crude reaction mixture was purified by silica gel column chromatography (EtOAc-hexane, 1:4) to provide the desired alkylation product 3a (107.1 mg, 0.405 mmol, 77%) as a clear colorless oil.
¹H NMR (400 MHz, CDCl3): δ = 7.18-7.08 (m, 3 H), 6.99 (d, J = 7.6 Hz, 1 H), 5.45 (d, J = 6.0 Hz, 1 H), 4.15 (dddd, J = 11.2, 4.8, 4.8, 1.6 Hz, 1 H), 3.98 (dd, J = 6.0, 2.0 Hz,
1 H), 3.80-3.73 (m, 1 H), 3.73 (d, J = 2.0 Hz, 3 H), 3.63 (d, J = 2.0 Hz, 3 H), 3.01-2.94 (m, 1 H), 2.69 (d, J = 16.4 Hz,
1 H) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 168.2, 167.3, 134.8, 134.6, 129.3, 127.4, 126.5, 124.7, 74.3, 63.7, 58.2, 53.0, 52.7, 28.8 ppm. This is a known compound and the spectral data are consistent with those reported in literature.5b

11

Representative Procedure and Spectroscopic Data - Synthesis of 2-(2,4-dihydro-1 H -isochromen-1-yl)-1-phenylethanone (5a)
In a sealable test tube equipped with a magnetic stir bar was charged Cu(OTf)2 (9.0 mg, 0.025 mmol), InCl3 (5.5 mg, 0.025 mmol), and NHPI (16.3 mg, 0.100 mmol). The reaction vessel was sealed and flushed with O2. The tube was attached to a balloon of O2 and charged with acetophenone (4a) (0.058 mL, 0.500 mmol) and isochroman (2a) (0.31 mL, 2.5 mmol). The test tube was placed in an oil bath set at 75 ˚C and was allowed to stir overnight. The reaction mixture was allowed to cooled to r.t., and the crude reaction mixture was purified by silica gel column chromatography (EtOAc-hexane, 1:5) to provide the desired alkylation product 5a (95.0 mg, 0.379 mmol, 75%) as a pale yellow oil.
¹H NMR (400 MHz, CDCl3): δ = 8.03-8.00 (m, 2 H), 7.59-7.55 (m, 1 H), 7.49-7.45 (m, 2 H), 7.22-7.18 (m, 2 H), 7.16-7.10 (m, 2 H), 5.51 (dd, J = 8.4, 3.2 Hz, 1 H), 4.12 (ddd, J = 10.8, 5.6, 3.6 Hz, 1 H), 3.82 (ddd, J = 3.6, 9.6, 11.2 Hz, 1 H), 3.63 (dd, J = 8.8, 16.6 Hz, 1 H), 3.33 (dd, J = 3.6, 16.0 Hz, 1 H), 3.03 (ddd, J = 5.6, 9.6, 15.6 Hz, 1 H), 2.73 (ddd, J = 3.6, 3.6, 16.4 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 198.3, 137.8, 137.4, 134.3, 133.4, 129.3, 128.8, 128.6, 126.8, 126.5, 124.8, 73.0, 63.8, 45.9, 29.3 ppm. This is a known compound and the spectral data are consistent with those reported in literature.5a

12

Previously, we proposed a similar intermediate for the oxidative arylation of cyclic benzyl amines with aryl boronic acids.6d

15

Metal salts are known to reductively decompose alkyl hydroperoxides to its corresponding alkyloxy radical. Conversely, metal salts can be oxidized by hydroperoxides and generate hydroperoxide radicals.7