Month 2014
Derivatization of Coumarins at the Benzenoid Ring in Aqueous Medium
d 9.23 (br. s, 1H), 7.30 (d with fine splitting, 1H), 7.06 (t with fine
splitting, 1H), 6.81 (d with fine splitting, 1H), 6.74 (t with fine
splitting, 1H), 5.72 (br s, 1H), 4.69 (t, J = 7.5 Hz, 1H), 2.99
(somewhat merged with DMSO H, 2H), 2.87 (m, 1H), 2.50–2.52
(m, 3H); 2.33 (m, 1H) and 2.20 (m, 1H). 13C NMR (125 MHz,
d6-DMSO): d 176.0, 155.4, 128.5, 127.4, 127.3, 119.0, 115.69,
56.5, and 39.2.
6-Hydroxycoumarin (4g).
Colorless solid, mp 249ꢀC
(CHCl3) (lit. 243–47ꢀC [26]); yield 84 mg, 52%. 1H NMR
(200 MHz, CDCl3): d 9.74 (s, disappeared on deuteration, 1H),
7.96 (d, J = 9.6 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 7.04–6.99
(m, 2H), and 6.42 (d, J = 9.6 Hz, 1H). LCMS: m/z 162.9 (M+ + 1).
6-Hydroxy-7-methylcoumarin (5).
Colorless solid, 179ꢀC
1
(CHCl3); yield 66 mg, 38%. H NMR (200 MHz, d6-DMSO): d
7.60 (d, J = 9.6 Hz, 1H), 7.12 (s, 1H), 6.85 (s, 1H), 6.36,
(d, J = 9.6 Hz, 1H), 5.44 (br. s, 1H), and 2.43 (s, 3H). LCMS:
m/z 177 (M+ + 1). Anal. Calcd for C10H8O3 C 68.18, H 4.58;
found C 68.32, H 4.51.
Biginelli condensation. The aldehyde (IV, 174 mg; 1 mmol)
was heated under reflux with 1.1 equivalent ethyl acetoacetate
(143mg; 1.1 mmol) and 1.5 equivalent urea (90 mg; 1.5 mmol) in
the presence of 10mol% FeCl3 (16 mg) in ethanol medium for 6 h
[19]. Then, the mixture was poured into cold water and
neutralized with bicarbonate. The precipitated ferric hydroxide
was removed, and the filtrate was extracted with ethyl acetate.
Upon chromatography (silica gel, 60–100 mesh), pure product
(4e) was obtained (160 mg; 50% yield) in ethyl acetate–petroleum
ether (1:1) eluate.
By stirring at room temperature for 24 h the same reactants in
dry dimethyl formamide in the presence of 6 equivalents (0.7 g)
of chlorotrimethyl silane [20], an improved yield (202 mg; 62%)
of the product was recorded. The structure was settled by spectral
studies.
6-Hydroxy-3,4-benzocoumarin (6).
218ꢀC (CH3OH); yield 117 mg, 55%. IR: nmax (KBr) 3387,
1698 cmꢁ1 1H NMR (200 MHz, d6-DMSO):
9.80, (s,
Colorless solid, mp
.
d
disappeared on deuteration, 1H), 8.30–8.22 (m, 2H), 7.94 (t,
J = 7.2 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 7.59 (d, J = 2.6 Hz, 1H),
7.27 (d, J = 9 Hz, 1H), and 6.99 (dd, J = 9 and 2.6 Hz, 2H). 13C
NMR (50 MHz, d6-DMSO): d 160.9, 154.7, 144.4, 135.8,
134.7, 130.7, 129.7, 122.9, 11.0, 118.9, 118.7, 108.6. LCMS:
m/z 235.1 (M+ + 23). Anal. Calcd for C13H8O3 C 73.58, H 3.80;
found C 73.48, H 3.81.
REFERENCES AND NOTES
Ethyl 6-methyl-2-oxo-4-[coumarin-6-yl]dihydropyrimidine-5-
carboxylate (4e).
Colorless solid, mp 248ꢀC (CH3OH). IR:
[1] Bhunia, S. C.; Patra, G. C.; Pal, S. C. Synth Commun 2011, 41
(24), 3678.
[2] (a) Wang, M. X.; Meng, X. M.; Zhu, M. Z.; Guo, Q. X. Chinese
Chem Lett 2007, 18, 1403; (b) Adhikari, S.; Ghosh, K. Tetrahedron Lett
2006, 47, 65.
[3] Amin, K. M.; Rahman, D. E. A.; Al-Eryani, Y. A. Bioorg Med
Chem 2008, 16, 5377.
[4] (a) Elbs, K. J Prakt Chem 1893, 48, 179; (b) Sethna, S. M.
Chem Rev 1951, 49(1), 91.
[5] (a) Ledderer, L. J Prakt Chem 1894, 50, 223; (b) Manasse,
O. Ber 1894, 27, 2409.
[6] Anastas, P. T.; Warner, J. C. Green Chemistry-Theory and
Practice; Oxford University Press: New York, 1998; 30.
[7] (a) Biginelli, P. Ber 1891, 24, 1317; (b) Biginelli, P. Ber 1893, 26, 447.
[8] Hantzsch, A. Chem Ber 1881, 14, 1627.
nmax (KBr) 3367, 3210, 1729, 1698, 1660, 1243, 1089, and
1
818 cmꢁ1. H NMR (500 MHz, d6-DMSO): d 9.26 (s, 1H), 8.11,
(d, J = 9.6Hz, 1H), 7.80 (s, 1H), 7.537 (s, 1H), 7.50 (d, J = 8.5 Hz,
1H), 7.39(d, J = 8.5 Hz, 1H), 6.48 (d, J = 9.6 Hz, 1H), 5.25
(d, J = 2.6 Hz, 1H), 3.97 (q, J = 7 Hz, 2H), 2.28 (s, 3H), and 1.09
(t, J = 7 Hz, 3H). 13C NMR (125MHz, d6-DMSO): d 165.2,
159.9, 152.7, 151.8, 148.8, 144.3, 141.3, 130.3, 125.9, 118.5,
116.5, 116.3, 98.8, 59.2, 53.6, 17.9, and 14.1. LCMS: m/z 329
(M+ + 1). Anal. Calcd for C17H16N2O3 C 62.19, H 4.91, N 8.53;
found C 62.81, H 4.77, N 8.50.
Hantzsch synthesis. A mixture of coumarin-6-carbaldehyde
(174mg, 1 mmol.), ethyl acetoacetate (260 mg, 4 mmol), and
ammonium acetate (110 mg, 1.5 mmol) in 20mL ethanol was
refluxed for 2 h. After the reaction was over, ~50 mL water was
added and extracted with ethyl acetate. The organic extract
was dried over anhydrous Na2SO4, solvent was removed, and the
residue recrystallized from chloroform.
[9] Dakin, H. D. J Am Chem Soc 1909, 42, 477.
[10] Sen, R.; Chakravarty, D. J Am Chem Soc 1928, 50, 2428.
[11] Calo, V.; Cimine, F.; Lopez, L.; Todesco P. E. J Chem Soc C
1971, 3652.
[12] This type of consideration is not important for weak electrophiles
like CCl2, HCHO, etc. (late T.S.).
Diethyl 4-[coumarin-6-yl]-2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate (4f).
Light yellow crystalline solid, mp
[13] Fuson, R. C.; Kneisley, J. W.; Kaiser, E. W. Org Synth 1955,
3, 209.
198ꢀC (CHCl3). Yield was 365 mg, 92%. IR: nmax (KBr) 3287,
3242, 1700, 1684, and 1110cmꢁ1. H NMR (500 MHz, CDCl3):
1
[14] (a) Valizadeh, H.; Vaghefi, S. Synth Commun 2009, 39(9),
1666; (b) Lay, L Synth Commun 2006, 36(15), 2203; (c) Shockravi, A.;
Valizadeh, H.; Heravi, M. M. Phosphorus Sulfur Silicon Relat Elem
2003, 178, 501; (d) Dubuffet, T.; Loutz, A.; Lavielle, G. Synth Commun
1999, 29, 929; (e) Oda, N.; Yoshida, Y.; Nagai, S.; Ueda, T.; Sakakibara, J.
Chem Pharm Bull 1987, 35, 1796; (f) Takeuchi, Y.; Ueda, N.; Uesugi, K.;
Abe, H.; Nishioka, H.; Harayama, T. Heterocycl 2003, 59, 217; (g) Shahidi,
F.; Tidwell, T. T. Can J Chem 1982, 60, 1092; (h) Harayama, T.; Nakatsuka,
K.; Nishioka, N.; Ishii, H. Chem Pharm Bull 1994, 42, 2170.
[15] Patel, H. S.; Patel, S. R. J Macromol Sci, Part A 1984, 21, 343.
[16] (a) Behrman, E. J. Beilstein J Org Chem 2006, 2, 22; (b)
Cingolani, E.; Schiavello, A.; Sebastiani, C. Gazz Chim Ital 1953, 83, 647;
(c) Salem, M. A.; Gemeay, A. H.; El-Daly, S. A. Monatsh Chem 1996,
127, 867; (d) Desai, R. B.; Sethna, S. J Indian Chem Soc 2 1951, 8, 213.
[17] Jones, M. Jr. Organic Chemistry; 2nd Edn., W. W. Norton &
Co.: New York. London, 2000; 855.
d 7.67 (d, J = 9.6 Hz, 1H), 7.48 (d, J = 8 Hz, 1H), 7.40 (s, 1H),
7.19 (d, J = 8 Hz, 1H), 6.37 (d, J = 9.6 Hz, 1H), 6.14 (br. S, 1H),
5.06 (s, 1H), 4.10 (m, 4H), 1.23 (d, J = 6 Hz, 6H). 13C NMR
(125MHz, CDCl3): d 167.4, 161.3, 152.5, 144.7, 144.4, 144.1,
132.1, 127.1, 118.2, 116.3, 116.0, 103.6, 59.9, 39.4, 19.6, and
14.3. HRMS: m/z calculated for 420.1418 C21H23NO6Na
[M+ + Na]; found 420.1417.
Dakin reaction. The saponified solution containing 1 mmol
of aldehyde (IV or V or VI) in 20% NaOH was cooled to ꢁ10ꢀC.
A slight excess (~1.2 equivalent) of 30% H2O2 solution was
added dropwise. The mixture was allowed to attain room
temperature and kept stirring for 2 h. An excess of H2O2 was
ensured (detected by acidified permanganate solution). Then, the
solution was acidified, extracted with ethyl acetate, and finally
purified by chromatography. The structures were established by
spectral analyses.
[18] Peter, J.; Jessup, C.; Bruce, P.; Jan, R.; Overman, L. E. Org
Synth 1988, 6, 95.
[19] Pal, S.; Pal, S. C. Acta Chim Slov 2011, 58, 596.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet