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Synlett 2004(9): 1584-1588  
DOI: 10.1055/s-2004-829081
LETTER
© Georg Thieme Verlag Stuttgart · New York

Coumarin-enaminoester Adducts: Structure Corrections (X-ray) and Some Novel Transformations. Synthesis of Annulated Tricyclic 2-Pyridones

Lyubomir D. Raeva, Wolfgang Freyb, Ivo C. Ivanov*a
a Faculty of Pharmacy, Medical University of Sofia, Dunav 2, BG-1000 Sofia, Bulgaria
Fax: +359(2)9879874; e-Mail: ivo43bg@yahoo.co.uk;
b Institut für Organische Chemie der Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
e-Mail: wolfgang.frey@po.uni-stuttgart.de;
Further Information

Publication History

Received 19 March 2004
Publication Date:
29 June 2004 (online)

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Abstract

By means of X-ray crystallographic analysis the correct structure of all three types of stable coumarin-enaminoester adducts 6, 10 and 11 and the corresponding spontaneous multistep heterocyclizations of ANRORC-type are reported. The initially formed adducts 3-5 undergo lactone ring opening as well as, in many cases, spontaneous transannular intramolecular Michael addition, to give 6, 10 and 11. A classic Michael addition of ethyl malonamate 12 to 3-substituted coumarins 1 followed by a lactone ring opening gives 13 as final product.

Key words

enamines - N-heterocycles - pyridines - pyrans - Michael addition - X-ray analysis

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X-ray Crystal Structure Analyses: atomic coordinates, bond lengths [Å] and angles [deg], anisotropic displacement parameters, hydrogen coordinates, torsion angles [deg] have been deposited at Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK, under deposition numbers CCDC 177460 for 6a, CCDC 177461 for 8a, CCDC 177459 for 10e, CCDC 181931 for 11a, CCDC 233450 for 13c, CCDC 177462 for 13h, CCDC 177463 for 15a, CCDC 177464 for 16a, CCDC 177464 for 17a [fax: +44 (1223)336033; homepage: http://www.ccdc.cam.ac.uk].

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(a) Typical Procedure for the Preparation of Coumarin-enaminoester Adducts (6a,c,e,f,h,i; 8a; 10c-f,h,i; 11a,c,i):
A mixture of 15 mmol of the corresponding coumarin 1a-i and 15 mmol of an enaminoester 2a-c in 40 mL anhyd EtOH was stirred (temperature and period of time are given in Table [1] ). After cooling, the separated crystals of the corresponding adduct were filtered, washed with cold EtOH and recrystallized, usually from EtOH. If a mixture of products was obtained (TLC monitoring), the solvent was removed in vacuo and the residue was separated by column chromatography on siliga gel.
(b) Systematic names: Ethyl 12-benzoyl-9-ethoxy-11-oxo-8-oxa-10-azatricyclo[7.3.1.0 [2] [7] ]trideca-2 (7),3,5-triene-13-carboxylate (10e); Ethyl {11-oxo-8-oxa-10-azatricyclo[7.3.1.0 [2] [7] ]trideca-2,4,6-trien-9-yl}acetate (11a).

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Ethyl 2-Amino-4-(2-hydroxyphenyl)-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylate (6a) (unpublished data): 1H NMR (400 MHz, DMSO-d 6): δ = 1.02 (t, J = 7.0 Hz, 3 H, CH3), 2.51 (d, 2 J = 16.0 Hz, 1 H, 5-HA), 2.80 (dd, 2 J = 16.0 Hz, 3 J = 7.3 Hz, 1 H, 5-HB), 3.99 (m, 2 H, OCH2), 4.35 (d, 3 J = 7.3 Hz, 1 H, 4-H), 6.67 (m, 1 H, 6′-H), 6.80 (m, 2 H, 3′-H, 5′-H), 6.99 (m, 1 H, 4′-H.), 6.00-8.00 (br, 2 H, NH2), 9.45 (s, 1 H, NH or OH), 9.59 (s, 1 H, OH or NH). 13C NMR (100.6 MHz, DMSO-d 6): δ = 13.5 (CH3), 28.7 (C-4), 36.1 (C-5), 57.4 (O-CH2), 74.9 (C-3), 114.0 (Carom.), 117.9 (Carom.), 125.5 (Carom.), 126.5 (Carom.), 128.4 (Carom.), 152.4 (C-2′), 153.4 (C-2.), 167.4 (C=O, ester), 170.0 (C=O, lactam).
Salient NMR signals: O-Acetyl derivative (15a): mp 170-172 °C (toluene). 1H NMR (300 MHz, DMSO-d 6): δ = 2.32 (s, 3 H, OCOCH3), 7.03-7.25 (m, 6 H, 4Harom and NH2), 9.73 (s, 1 H, lactam-NH). N-Acetyl derivative (16a): mp 184-186 °C (EtOH). 1H NMR (300 MHz, DMSO-d 6): δ = 2.21 (s, 3 H, NCOCH3), 9.61 (br s, 1 H, OH), 10.68 (s, 1 H, amide-NH), 11.49 (s, 1 H, lactam-NH). O,N-Diacetyl derivative (17a): mp 180-181 °C (EtOH). 1H NMR (300 MHz, CDCl3): δ = 2.23 (s, 3 H, NCOCH3), 2.34 (s, 3 H, OCOCH3), 10.96 (s, 1 H, amide-NH), 11.98 (s, 1 H, lactam-NH). 13C NMR (75 MHz, CDCl3): δ = 21.0 (OCOCH3), 25.3 (NCOCH3).

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Ethyl 2-Amino-4-(2-hydroxy-5-nitrophenyl)-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylate (6f) (unpublished data): 1H NMR (400 MHz, DMSO-d 6): δ = 1.04 (m, 3 H, CH3), 2.50 (d, 2 J = 16.2 Hz, 1 H, 5-HA), 2.80 (dd, 3 J = 7.3 Hz, 2 J = 16.2 Hz, 1 H, 5-HB), 3.95 (m, 2 H, OCH2), 4.40 (d, 3 J = 7.3 Hz, 1 H, 4-H), 7.01 (d, 1 H, 3′-H), 7.75 (s, 1 H, 6′-H), 8.03 (d, 1 H, 4′-H.), 6.20-7.80 (br, 2 H, NH2), 9.80 (s, 1 H, NH or OH), 11.35 (br s, 1 H, OH or NH). 13C NMR (100.6 MHz, DMSO-d 6): δ = 14.8 (CH3), 30.5 (C-4), 36.9 (C-5), 58.6 (O-CH2), 75.0 (C-3), 115.9
(Carom.-3′), 123.1 (Carom.-6′), 124.7 (Carom.-4′), 131.7
(Carom.-1′), 139.8 (Carom.-5′), 154.6 (C-2), 162.0 (Carom.-2′), 168.2 (C=O, ester), 170.3 (C=O, lactam).
Salient 1H NMR signals: N-Acetyl derivative (16b): mp 218-220 °C (2-PrOH). 1H NMR (250 MHz, DMSO-d 6): δ = 2.23 (s, 3 H, NCOCH3), 10.72 (s, 1 H, amide-NH), 11.40 (s, 1 H, lactam-NH), 11.5 (br s, 1 H, OH). O,N-Diacetyl derivative (17b): mp 165-166.5 °C (2-PrOH). 1H NMR (250 MHz, CDCl3): δ = 2.29 (s, 3 H, NCOCH3), 2.40 (s, 3 H, OCOCH3), 11.12 (s, 1 H, amide-NH), 12.01 (s, 1 H, lactam-NH).

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Raev, L. D.; Ivanov, I. C. Third National Congress of Pharmacy (Abstracts), 17-19 October 1996, Sofia - Panichishte (Bulgaria); poster 11.P5.