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

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.

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

References and Notes

<A NAME="RS08908ST-1">1</A>

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

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<A NAME="RS08908ST-3G">3g</A> Li C.-J. Acc. Chem. Res.  2008,  in press

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<A NAME="RS08908ST-9">9</A>

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.

<A NAME="RS08908ST-10">10</A>

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

<A NAME="RS08908ST-11">11</A>

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

<A NAME="RS08908ST-12">12</A>

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

Although alcohol 6 was not observed during the optimization process, we considered it to be a potential intermediate since benzylic alcohols are known to undergo alkylation with malonates and diketones in the presence of metal salts. For recent examples, see:

<A NAME="RS08908ST-13A">13a</A> Yasuda M. Somyo T. Baba A. Angew. Chem. Int. Ed.  2006,  45:  793 

<A NAME="RS08908ST-13B">13b</A> Rueping M. Nachtsheim BJ. Kuenkel A. Org. Lett.  2007,  9:  825 

<A NAME="RS08908ST-13C">13c</A> Kischel J. Mertins K. Michalik D. Zapf A. Beller M. Adv. Synth. Catal.  2007,  349:  865 

<A NAME="RS08908ST-13D">13d</A> Huang W. Wang J. Shen Q. Zhou X. Tetrahedron Lett.  2007,  48:  3969 

<A NAME="RS08908ST-13E">13e</A> Noji M. Konno Y. Ishii K. J. Org. Chem.  2007,  72:  5161 

<A NAME="RS08908ST-14">14</A> For the preparation of benzylic alcohol 6, see: Xu YC. Lebeau E. Gillard JW. Attardo G. Tetrahedron Lett.  1993,  34:  3841 

<A NAME="RS08908ST-15">15</A>

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

<A NAME="RS08908ST-16">16</A> Jones CW. Application of Hydrogen Peroxide and Derivatives, The Royal Society of Chemistry; Cambridge: 1999.