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Oxidative radical cyclisation of beta-Keto-esters using ceric ammonium nitrate (CAN) ; gamma-lactams via 5-endo-trig radical cyclisation

SyntheticPage 182 (2001)
Submitted 19th Dec 2001, published 20th Dec 2001

John P. McDonagh (,
A contribution from the Clark Group, Warwick

Reaction Scheme

Chemicals Used
Ceric ammonium nitrate (Aldrich), N-(1-Isopropyl-vinyl)-N-(4-methoxy-benzyl)-malonamic acid methyl ester, acetonitrile or methanol

Ceric ammonium nitrate (723 mg, 1.32 mmol) was added to a stirring solution of the N-(1-Isopropyl-vinyl)-N-(4-methoxy-benzyl)-malonamic acid methyl ester (100 mg, 0.33 mmol) in methanol or acetonitrile (4 ml) and stirred at room temperature for 20 minutes. The resulting solution was dropped onto H2O (25 ml), extracted with ethyl acetate (25 ml x 3), dried with MgSO4 and reduced to dryness in vacuo. Purification was carried out by flash chromatogtraphy (1:1 petroleum ether : ethyl acetate), to give the following cyclic products (Methoxy-lactam 74 mg, 67 %, Hydroxy-lactam 100 mg, 95 %).

Author's Comments
This simple procedure has been carried out sucessfully for a number of other cyclic and bicyclic enamide precursors. Also, other common alcohols have been used as solvents to "trap-out" the final product. Generally, the procedure using acetonitrile as the solvent does not require any purification after work-up. This reaction has been scaled up from 20 mg to 2 g without much variation in the overall yield or reaction time. Also, the use of more than 4 equvalents of CAN has a deterimental effect on the yield of the product.

Methoxy-lactam: 1H NMR (250 MHz, CDCl3) d 7.48 (1H, s, CH=C), 7.37 (2H, d, J = 8.6 Hz, CHCHCOCH3), 6.77 (2H, d, J = 8.6 Hz, CH=COCH3), 4.32 (2H, s, CH2N), 3.86 (3H, s, OCH3), 3.75 (3H, s, OCH3), 2.74 (3H, s, OCH3), 2.20 (1H, sep, J = 6.7 Hz, CH(CH3)2), 1.07 (3H, d, J = 6.7 Hz, CHCH3), 0.43 (3H, d, J = 6.7 Hz, CHCH3) Hydroxy-lactam: 1H NMR (250 MHz, CDCl3) d 7.54 (1H, s, CH=C), 7.31 (2H, d, J = 8.6 Hz, CHCHCOCH3), 6.75 (2H, d, J = 8.6 Hz, CH=COCH3), 4.43 (1H, d, J = 15.0 Hz, CHHN), 4.30 (1H, d, J = 15.0 Hz, CHHN), 3.79 (3H, s, OCH3), 3.73 (3H, s, OCH3), 2.14 (1H, sep, J = 6.8 Hz, CH(CH3)2), 1.05 (3H, d, J = 6.8 Hz, CHCH3), 0.35 (3H, d, J = 6.8 Hz, CHCH3)

Lead Reference
A. Dí Annibale, A. Pesce, S. Resta, C. Trogolo, Tetrahedron Lett., 1997, 38, 1829

Other References
V. Nair, J. Mattew, J. Chem. Soc., Perkin Trans. 1, 1995, 187

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