Diels±Alder trapping of 3-methylenequinolin-2,4-dione: a facile synthesis of pyranoquinolinones and spiroquinolinediones Vijay Nair, a,p P. M. Treesa, a C. N. Jayan, a Nigam P. Rath, b M. Vairamani c and S. Prabhakar c a Organic Chemistry Division, Regional Research Laboratory CSIR), Trivandrum 695 019, India b Department of Chemistry, University of Missouri, St Louis, MO 63121-4499, USA c Analytical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad, India Received 23 March 2001; revised 6 June 2001; accepted 28 June 2001 Abstract Ð3-Methylenequinolin-2,4-dione generated in situ by Knoevenagel condensation of 4-hydroxyquinoline with formaldehyde is trapped by Diels±Alder cycloaddition to provide spiroquinolinediones and pyranoquinolinones. q 2001 Elsevier Science Ltd. All rights reserved. 1. Introduction The recognition of the synthetic potential of heterocyclic quinone methides has aroused considerable interest in their generation and subsequent transformations. 1 Quinoli- none quinone methides constitute such a class of versatile synthons for the synthesis of naturally occurring bio- logically active pyranoquinolinones, dimeric quinolinone alkaloids and other polycyclic heterocycles. Recently, it was reported that pyranoquinolinones zanthosimuline and huajiaosimuline 2 Fig. 1) isolated from Zanthoxylum simulans exhibit cytotoxic activity against human cancer cells. 3 The known methods for the generation of quinolinone quinone methides include DDQ oxidation of 3-alkyl-4- hydroxy quinolinone, 4 elimination of a secondary amine from a Mannich base, pyrolysis of ¯indersine derivatives, or bisquinolinone 5 and Knoevenagel condensation of 4-hydroxyquinolinone with an aldehyde. 6 In spite of the work by various groups to exploit the versatility of quinolinone quinone methides, barring the reports by Grundon and co-workers, 7 no effort has been made to study the cycloaddition pro®le of this methide. As a part of our general interest in the chemistry of quinonoid compounds and their cycloaddition reactions in particular, 8 we have investigated the cycloaddition pro®le of this system and the results are presented here. 2. Results and discussion Our investigations began with the reaction of N-methyl-3- methylene-quinolin-2,4-dione 3 with cyclopentadiene. When 4-hydroxy-N-methylquinolin-2-one 1 was treated with paraformaldehyde in re¯uxing dioxane in the presence of cyclopentadiene, the in situ generated quinone methide 3 underwent facile hetero Diels±Alder reaction with cyclopentadiene in a chemo- and regioselective manner to afford a colourless product 5a in 84% yield Scheme 1). The structure of the cycloadduct was established by spectro- scopic analysis. The IR spectrum of the product showed a strong absorption at 1639 cm 21 . In the 13 C NMR spectrum, the carbonyl carbon gave a signal at d 163.41. The signal due to the sp 3 carbon C-1 was discernible at d 83.03. The regiochemistry of the product was ascertained with the help of 1 H± 1 H relayed COSY spectrum. The correlation spec- trum clearly showed the connectivity between the different sets of protons. The most diagnostic of these is the connec- tivity shown by the ring junction proton on C-1 d 5.23), which is connected to the ole®nic proton on C-2 d 6.07) and the ring junction proton on C-5 d 2.83). Tetrahedron 57 2001) 7711±7717 Pergamon TETRAHEDRON 0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved. PII: S0040-402001)00704-9 N O O Me N O O Me O zanthosimuline huajiaosimuline Figure 1. Keywords: cycloaddition; dienes; enol ethers; quinolines. p Corresponding author. Tel.: 191-471-490-406; fax: 191-471-491-712; e-mail: gvn@csrrltrd.ren.nic.in